Abstract
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders. The pathological hallmarks of AD are amyloid-beta (Aβ) plaques and tau protein tangles, which cause neurodegeneration and lead to cognitive decline. The distinguished role of Aβ plaques in the onset of the disease, especially in familial AD, alongside the genetic complexity of AD, underscores the need for precise and targeted genetic interventions targeting Aβ. This review first highlights the amyloidogenic and non-amyloidogenic pathways and inflammatory mechanisms contributing to Aβ accumulation. It also introduces the role of genetic variants such as amyloid precursor protein (APP), presenilin (PSEN1), PSEN2, and Apolipoprotein E (APOE) alongside the molecular and cellular mechanisms involved in Aβ pathology. Then, gene therapy techniques are discussed for their potential to target Aβ either directly by inhibiting its production or enhancing its degradation or indirectly by targeting APOE, inflammatory pathways, and neurotrophic factors. While these approaches show significant preclinical promise, challenges such as timing, safety, and delivery across the blood–brain barrier persist and need further investigation.
Acknowledgments
The figures in this article were prepared with the help of Servier Medical Art https://smart.servier.com/ under CC BY 4.0 license https://creativecommons.org/licenses/by/4.0.
-
Research ethics: Not applicable.
-
Informed consent: Not applicable.
-
Author contributions: P.P. conceptualized the review, drafted the initial manuscript, and contributed to the initial title proposal. P.A. revised and finalized the title, thoroughly edited the manuscript, and provided structural and linguistic improvements to refine the content. N.R. supervised the project, provided critical feedback, and guided the overall development and direction of the review. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: Grammarly and Quill bot were adopted minorly in some parts to improve the language.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: None declared.
-
Data availability: Not applicable.
References
Al-Atrache, Z., Lopez, D.B., Hingley, S.T., and Appelt, D.M. (2019). Astrocytes infected with Chlamydia pneumoniae demonstrate altered expression and activity of secretases involved in the generation of β-amyloid found in Alzheimer disease. BMC Neurosci. 20: 6, https://doi.org/10.1186/s12868-019-0489-5.Search in Google Scholar PubMed PubMed Central
Ali, N.H., Al-Kuraishy, H.M., Al-Gareeb, A.I., Alnaaim, S.A., Alexiou, A., Papadakis, M., Khalifa, A.A., Saad, H.M., and Batiha, G.E. (2024). Neprilysin inhibitors and risk of Alzheimer’s disease: A future perspective. J. Cell. Mol. Med. 28: e17993, https://doi.org/10.1111/jcmm.17993.Search in Google Scholar PubMed PubMed Central
Allen, S.J. and Dawbarn, D. (2009). Chapter 4: Pathophysiology of Alzheimer’s disease. In: Waldemar, G. and Burns, A. (Eds.), Alzheimer’s disease, 1st ed. Oxford University Press, Oxford, UK, pp. 27–35.Search in Google Scholar
Alzheimer’s disease international (2021). Dementia Stat., Available at:https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/.Search in Google Scholar
Amelimojarad, M., Amelimojarad, M., and Cui, X. (2024). The emerging role of brain neuroinflammatory responses in Alzheimer’s disease. Front Aging Neurosci. 16: 1391517, https://doi.org/10.3389/fnagi.2024.1391517.Search in Google Scholar PubMed PubMed Central
Arora, S., Layek, B., and Singh, J. (2021). Design and validation of liposomal ApoE2 gene delivery system to evade blood-brain barrier for effective treatment of Alzheimer’s disease. Mol. Pharm. 18: 714–725, https://doi.org/10.1021/acs.molpharmaceut.0c00461.Search in Google Scholar PubMed PubMed Central
Arora, S., Kanekiyo, T., and Singh, J. (2022). Functionalized nanoparticles for brain targeted BDNF gene therapy to rescue Alzheimer’s disease pathology in transgenic mouse model. Int. J. Biol. Macromol. 208: 901–911, https://doi.org/10.1016/j.ijbiomac.2022.03.203.Search in Google Scholar PubMed
Ashrafian, H., Zadeh, E.H., and Khan, R.H. (2021). Review on Alzheimer’s disease: inhibition of amyloid beta and tau tangle formation. Int. J. Biol. Macromol. 167: 382–394, https://doi.org/10.1016/j.ijbiomac.2020.11.192.Search in Google Scholar PubMed
Ataei, B., Hokmabadi, M., Asadi, S., Asadifard, E., Aghaei Zarch, S.M., Najafi, S., and Bagheri-Mohammadi, S. (2024). A review of the advances, insights, and prospects of gene therapy for Alzheimer’s disease: a novel target for therapeutic medicine. Gene 912: 148368, https://doi.org/10.1016/j.gene.2024.148368.Search in Google Scholar PubMed
Atagi, Y., Liu, C.C., Painter, M.M., Chen, X.F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S.S., Xu, H., et al.. (2015). Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290: 26043–26050, https://doi.org/10.1074/jbc.m115.679043.Search in Google Scholar PubMed PubMed Central
Bagaria, J., Bagyinszky, E., and An, S.S.A. (2022). Genetics, functions, and clinical impact of presenilin-1 (PSEN1) gene. Int. J. Mol. Sci. 23, https://doi.org/10.3390/ijms231810970.Search in Google Scholar PubMed PubMed Central
Ballinger, C.A., Connell, P., Wu, Y., Hu, Z., Thompson, L.J., Yin, L.Y., and Patterson, C. (1999). Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol. Cell. Biol. 19: 4535–4545, https://doi.org/10.1128/mcb.19.6.4535.Search in Google Scholar PubMed PubMed Central
Baranello, R.J., Bharani, K.L., Padmaraju, V., Chopra, N., Lahiri, D.K., Greig, N.H., Pappolla, M.A., and Sambamurti, K. (2015). Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr. Alzheimer Res. 12: 32–46, https://doi.org/10.2174/1567205012666141218140953.Search in Google Scholar PubMed PubMed Central
Bekris, L.M., Yu, C.E., Bird, T.D., and Tsuang, D.W. (2010). Genetics of Alzheimer disease. J. Geriatr. Psychiatry Neurol. 23: 213–227, https://doi.org/10.1177/0891988710383571.Search in Google Scholar PubMed PubMed Central
Benilova, I. and De Strooper, B. (2013). Neuroscience. Promiscuous Alzheimer’s amyloid: yet another partner. Science 341: 1354–1355, https://doi.org/10.1126/science.1244166.Search in Google Scholar PubMed
Bergen, J.M., Park, I.K., Horner, P.J., and Pun, S.H. (2008). Nonviral approaches for neuronal delivery of nucleic acids. Pharm. Res. 25: 983–998, https://doi.org/10.1007/s11095-007-9439-5.Search in Google Scholar PubMed PubMed Central
Bradshaw, E.M., Chibnik, L.B., Keenan, B.T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L.L., Imboywa, S., Lee, M., Von Korff, A., et al.. (2013). CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16: 848–850, https://doi.org/10.1038/nn.3435.Search in Google Scholar PubMed PubMed Central
Bu, G. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10: 333–344, https://doi.org/10.1038/nrn2620.Search in Google Scholar PubMed PubMed Central
Busciglio, J., Gabuzda, D.H., Matsudaira, P., and Yankner, B.A. (1993). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci USA 90: 2092–2096, https://doi.org/10.1073/pnas.90.5.2092.Search in Google Scholar PubMed PubMed Central
Cacabelos, R. (2020). How plausible is an Alzheimer’s disease vaccine? Expert Opin. Drug Discov. 15: 1–6, https://doi.org/10.1080/17460441.2019.1667329.Search in Google Scholar PubMed
Cacace, R., Sleegers, K., and Van Broeckhoven, C. (2016). Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 12: 733–748, https://doi.org/10.1016/j.jalz.2016.01.012.Search in Google Scholar PubMed
Cai, Y., An, S.S., and Kim, S. (2015). Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders. Clin. Interv. Aging. 10: 1163–1172, https://doi.org/10.2147/cia.s85808.Search in Google Scholar PubMed PubMed Central
Carty, N., Nash, K.R., Brownlow, M., Cruite, D., Wilcock, D., Selenica, M.L., Lee, D.C., Gordon, M.N., and Morgan, D. (2013). Intracranial injection of AAV expressing NEP but not IDE reduces amyloid pathology in APP+PS1 transgenic mice. PLoS One 8: e59626, https://doi.org/10.1371/journal.pone.0059626.Search in Google Scholar PubMed PubMed Central
Chanana, N. and Pati, U. (2018). ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing. J. Cell. Biochem. 119: 4615–4626, https://doi.org/10.1002/jcb.26630.Search in Google Scholar PubMed
Chang, J.L., Hinrich, A.J., Roman, B., Norrbom, M., Rigo, F., Marr, R.A., Norstrom, E.M., and Hastings, M.L. (2018). Targeting amyloid-β precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-β production. Mol. Ther. 26: 1539–1551, https://doi.org/10.1016/j.ymthe.2018.02.029.Search in Google Scholar PubMed PubMed Central
Chen, X., Hu, Y., Cao, Z., Liu, Q., and Cheng, Y. (2018). Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Front Immunol. 9: 2122, https://doi.org/10.3389/fimmu.2018.02122.Search in Google Scholar PubMed PubMed Central
Chen, W., Hu, Y., and Ju, D. (2020). Gene therapy for neurodegenerative disorders: advances, insights and prospects. Acta Pharm. Sin. B 10: 1347–1359, https://doi.org/10.1016/j.apsb.2020.01.015.Search in Google Scholar PubMed PubMed Central
Cheng, S., Tereshchenko, J., Zimmer, V., Vachey, G., Pythoud, C., Rey, M., Liefhebber, J., Raina, A., Streit, F., Mazur, A., et al.. (2018). Therapeutic efficacy of regulable GDNF expression for Huntington’s and Parkinson’s disease by a high-induction, background-free “GeneSwitch” vector. Exp. Neurol. 309: 79–90, https://doi.org/10.1016/j.expneurol.2018.07.017.Search in Google Scholar PubMed
Cissé, M., Duplan, E., Lorivel, T., Dunys, J., Bauer, C., Meckler, X., Gerakis, Y., Lauritzen, I., and Checler, F. (2017). The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model. Mol. Psychiatry 22: 1562–1575, https://doi.org/10.1038/mp.2016.152.Search in Google Scholar PubMed PubMed Central
Citron, M., Vigo-Pelfrey, C., Teplow, D.B., Miller, C., Schenk, D., Johnston, J., Winblad, B., Venizelos, N., Lannfelt, L., and Selkoe, D.J. (1994). Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc. Natl Acad Sci USA 91: 11993–11997, https://doi.org/10.1073/pnas.91.25.11993.Search in Google Scholar PubMed PubMed Central
Cochran, J.N., Rush, T., Buckingham, S.C., and Roberson, E.D. (2015). The Alzheimer’s disease risk factor CD2AP maintains blood-brain barrier integrity. Hum. Mol. Genet. 24: 6667–6674, https://doi.org/10.1093/hmg/ddv371.Search in Google Scholar PubMed PubMed Central
Colucci-D’Amato, L., Speranza, L., and Volpicelli, F. (2020). Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int. J. Mol. Sci. 21, https://doi.org/10.3390/ijms21207777.Search in Google Scholar PubMed PubMed Central
Cozaru, G.C., Aşchie, M., Mitroi, A.F., Poinăreanu, I., and Gorduza, E.V. (2016). Ethical and genetic aspects regarding presymptomatic testing for neurodegenerative diseases. Rev. Med. Chir. Soc. Med. Nat. Iasi 120: 15–22.Search in Google Scholar
Crouch, P.J., Blake, R., Duce, J.A., Ciccotosto, G.D., Li, Q.X., Barnham, K.J., Curtain, C.C., Cherny, R.A., Cappai, R., Dyrks, T., et al.. (2005). Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J. Neurosci. 25: 672–679, https://doi.org/10.1523/jneurosci.4276-04.2005.Search in Google Scholar
Cummings, J., Ritter, A., and Zhong, K. (2018). Clinical trials for disease-modifying therapies in Alzheimer’s disease: a primer, lessons learned, and a blueprint for the future. J. Alzheimers Dis. 64: S3–s22, https://doi.org/10.3233/jad-179901.Search in Google Scholar PubMed PubMed Central
Cummins, T.D., Wu, K.Z.L., Bozatzi, P., Dingwell, K.S., Macartney, T.J., Wood, N.T., Varghese, J., Gourlay, R., Campbell, D.G., Prescott, A., et al.. (2018). PAWS1 controls cytoskeletal dynamics and cell migration through association with the SH3 adaptor CD2AP. J. Cell Sci. 131, https://doi.org/10.1242/jcs.202390.Search in Google Scholar PubMed PubMed Central
Dobson, J. (2006). Gene therapy progress and prospects: magnetic nanoparticle-based gene delivery. Gene Ther. 13: 283–287, https://doi.org/10.1038/sj.gt.3302720.Search in Google Scholar PubMed
Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., et al.. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369: 341–350, https://doi.org/10.1056/nejmoa1210951.Search in Google Scholar
Doshi, V., Joshi, G., Sharma, S., and Choudhary, D. (2024). Gene therapy: an alternative to treat Alzheimer’s disease. Naunyn. Schmiedebergs Arch. Pharmacol. 397: 3675–3693, https://doi.org/10.1007/s00210-023-02873-z.Search in Google Scholar PubMed
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., and Lambert, J.C. (2019). The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol. 138: 221–236, https://doi.org/10.1007/s00401-019-02004-0.Search in Google Scholar PubMed PubMed Central
Dropulić, B., Hĕrmánková, M., and Pitha, P.M. (1996). A conditionally replicating HIV-1 vector interferes with wild-type HIV-1 replication and spread. Proc. Natl. Acad. Sci. U. S. A. 93: 11103–11108, https://doi.org/10.1073/pnas.93.20.11103.Search in Google Scholar PubMed PubMed Central
Duan, Y., Ye, T., Qu, Z., Chen, Y., Miranda, A., Zhou, X., Lok, K.C., Chen, Y., Fu, A.K.Y., Gradinaru, V., et al.. (2022). Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice. Nat. Biomed. Eng. 6: 168–180, https://doi.org/10.1038/s41551-021-00759-0.Search in Google Scholar PubMed
Duran-Aniotz, C., Poblete, N., Rivera-Krstulovic, C., Ardiles Á, O., Díaz-Hung, M.L., Tamburini, G., Sabusap, C.M.P., Gerakis, Y., Cabral-Miranda, F., Diaz, J., et al.. (2023). The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis. Mol. Ther. 31: 2240–2256, https://doi.org/10.1016/j.ymthe.2023.03.028.Search in Google Scholar PubMed PubMed Central
Dykens, J.A. (1994). Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implications for neurodegeneration. J. Neurochem. 63: 584–591, https://doi.org/10.1046/j.1471-4159.1994.63020584.x.Search in Google Scholar PubMed
Eckert, A., Schulz, K.L., Rhein, V., and Götz, J. (2010). Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol. Neurobiol. 41: 107–114, https://doi.org/10.1007/s12035-010-8109-5.Search in Google Scholar PubMed PubMed Central
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J.P., Petzold, G.C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al.. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24: 312–325, https://doi.org/10.1038/s41593-020-00783-4.Search in Google Scholar PubMed PubMed Central
Faingold, C.L. (2014). Chapter 7 – network control mechanisms: cellular inputs, neuroactive substances, and synaptic changes. In: Faingold, C.L. and Blumenfeld, H. (Eds.). Neuronal Networks in brain function, CNS disorders, and therapeutics. Academic Press, San Diego, pp. 91–101.10.1016/B978-0-12-415804-7.00007-1Search in Google Scholar
Falkevall, A., Alikhani, N., Bhushan, S., Pavlov, P.F., Busch, K., Johnson, K.A., Eneqvist, T., Tjernberg, L., Ankarcrona, M., and Glaser, E. (2006). Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J. Biol. Chem. 281: 29096–29104, https://doi.org/10.1074/jbc.m602532200.Search in Google Scholar
Fan, Z., Brooks, D.J., Okello, A., and Edison, P. (2017). An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain 140: 792–803, https://doi.org/10.1093/brain/aww349.Search in Google Scholar PubMed PubMed Central
Fan, F., Liu, H., Shi, X., Ai, Y., Liu, Q., and Cheng, Y. (2022). The efficacy and safety of Alzheimer’s disease therapies: an updated umbrella review. J. Alzheimers Dis. 85: 1195–1204, https://doi.org/10.3233/jad-215423.Search in Google Scholar PubMed
Fan, F.C., Liu, L.M., Guo, M., Du, Y., Chen, Y.W., Loh, Y.P., and Cheng, Y. (2025). Neurotrophic factor-α1/carboxypeptidase E controls progression and reversal of Alzheimer’s disease pathogenesis in mice. Theranostics 15: 2279–2292, https://doi.org/10.7150/thno.99908.Search in Google Scholar PubMed PubMed Central
Fargali, S., Sadahiro, M., Jiang, C., Frick, A.L., Indall, T., Cogliani, V., Welagen, J., Lin, W.J., and Salton, S.R. (2012). Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis. J. Mol. Neurosci. 48: 654–659, https://doi.org/10.1007/s12031-012-9790-9.Search in Google Scholar PubMed PubMed Central
Feldman, H.H. and Lane, R. (2007). Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 78: 1056–1063, https://doi.org/10.1136/jnnp.2006.099424.Search in Google Scholar PubMed PubMed Central
Fernández-Morales, J.C., Arranz-Tagarro, J.A., Calvo-Gallardo, E., Maroto, M., Padín, J.F., and García, A.G. (2012). Stabilizers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer’s disease. ACS Chem. Neurosci. 3: 873–883, https://doi.org/10.1021/cn3001069.Search in Google Scholar PubMed PubMed Central
Fišar, Z. (2022). Linking the amyloid, tau, and mitochondrial hypotheses of Alzheimer’s disease and identifying promising drug targets. Biomolecules. 12, https://doi.org/10.3390/biom12111676.Search in Google Scholar PubMed PubMed Central
Folch, J., Ettcheto, M., Petrov, D., Abad, S., Pedrós, I., Marin, M., Olloquequi, J., and Camins, A. (2018). Review of the advances in treatment for Alzheimer disease: strategies for combating β-amyloid protein. Neurologia (Engl Ed). 33: 47–58, https://doi.org/10.1016/j.nrleng.2015.03.019.Search in Google Scholar
Francis, P.T., Palmer, A.M., Snape, M. and Wilcock, G.K. (1999). The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatr. 66: 137, https://doi.org/10.1136/jnnp.66.2.137.Search in Google Scholar PubMed PubMed Central
Frost, G.R. and Li, Y.M. (2017). The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol. 7, https://doi.org/10.1098/rsob.170228.Search in Google Scholar PubMed PubMed Central
Gao, L., Zhang, Y., Sterling, K., and Song, W. (2022). Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential. Transl. Neurodegener. 11: 4, https://doi.org/10.1186/s40035-022-00279-0.Search in Google Scholar PubMed PubMed Central
Gerakis, Y. (2016). Stress réticulaire et maladie d’Alzheimer: contribution du facteur de transcription XBP-1s, Doctoral dissertation. Nice, France, COMUE Université Côte d’Azur.Search in Google Scholar
Gomazkov, O.A. (2012). Neurotrophins: the therapeutic potential and concept of minipeptides. Neurochem. J. 6: 163–172, https://doi.org/10.1134/s1819712412030075.Search in Google Scholar
González-Reyes, R.E., Nava-Mesa, M.O., Vargas-Sánchez, K., Ariza-Salamanca, D., and Mora-Muñoz, L. (2017). Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front Mol. Neurosci. 10: 427, https://doi.org/10.3389/fnmol.2017.00427.Search in Google Scholar PubMed PubMed Central
Goodwin, J.L., Uemura, E., and Cunnick, J.E. (1995). Microglial release of nitric oxide by the synergistic action of beta-amyloid and IFN-gamma. Brain Res. 692: 207–214, https://doi.org/10.1016/0006-8993(95)00646-8.Search in Google Scholar PubMed
Griciuc, A., Federico, A.N., Natasan, J., Forte, A.M., McGinty, D., Nguyen, H., Volak, A., LeRoy, S., Gandhi, S., Lerner, E.P., et al.. (2020). Gene therapy for Alzheimer’s disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation. Hum. Mol. Genet. 29: 2920–2935, https://doi.org/10.1093/hmg/ddaa179.Search in Google Scholar PubMed PubMed Central
Gu, L. and Guo, Z. (2013). Alzheimer’s Aβ42 and Aβ40 peptides form interlaced amyloid fibrils. J. Neurochem. 126: 305–311, https://doi.org/10.1111/jnc.12202.Search in Google Scholar PubMed PubMed Central
Guan, H., Liu, Y., Daily, A., Police, S., Kim, M.H., Oddo, S., LaFerla, F.M., Pauly, J.R., Murphy, M.P., and Hersh, L.B. (2009). Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer’s disease. J. Neurosci. Res. 87: 1462–1473, https://doi.org/10.1002/jnr.21944.Search in Google Scholar PubMed PubMed Central
Gulisano, W., Maugeri, D., Baltrons, M.A., Fà, M., Amato, A., Palmeri, A., D’Adamio, L., Grassi, C., Devanand, D.P., Honig, L.S., et al.. (2018). Role of amyloid-β and tau proteins in Alzheimer’s disease: confuting the amyloid cascade. J. Alzheimers Dis. 64: S611–s631, https://doi.org/10.3233/jad-179935.Search in Google Scholar
Gustavsson, A., Norton, N., Fast, T., Frölich, L., Georges, J., Holzapfel, D., Kirabali, T., Krolak-Salmon, P., Rossini, P.M., Ferretti, M.T., et al.. (2023). Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement 19: 658–670, https://doi.org/10.1002/alz.12694.Search in Google Scholar PubMed
Habib, N., McCabe, C., Medina, S., Varshavsky, M., Kitsberg, D., Dvir-Szternfeld, R., Green, G., Dionne, D., Nguyen, L., Marshall, J.L., et al.. (2020). Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23: 701–706, https://doi.org/10.1038/s41593-020-0624-8.Search in Google Scholar PubMed PubMed Central
Hampel, H., Mesulam, M.M., Cuello, A.C., Farlow, M.R., Giacobini, E., Grossberg, G.T., Khachaturian, A.S., Vergallo, A., Cavedo, E., Snyder, P.J., et al.. (2018). The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141: 1917–1933, https://doi.org/10.1093/brain/awy132.Search in Google Scholar PubMed PubMed Central
Hampel, H., Mesulam, M.M., Cuello, A.C., Khachaturian, A.S., Vergallo, A., Farlow, M.R., Snyder, P.J., Giacobini, E., and Khachaturian, Z.S. (2019). Revisiting the cholinergic hypothesis in Alzheimer’s disease: emerging evidence from translational and clinical research. J. Prev. Alzheimers Dis. 6: 2–15, https://doi.org/10.14283/jpad.2018.43.Search in Google Scholar PubMed
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S.H., Villemagne, V.L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al.. (2021). The amyloid-β pathway in Alzheimer’s disease. Mo.l Psychiatry 26: 5481–5503, https://doi.org/10.1038/s41380-021-01249-0.Search in Google Scholar PubMed PubMed Central
Han, X., Zhang, T., Liu, H., Mi, Y., and Gou, X. (2020). Astrocyte senescence and Alzheimer’s disease: a review. Front Aging Neurosci. 12: 148, https://doi.org/10.3389/fnagi.2020.00148.Search in Google Scholar PubMed PubMed Central
Hao, W., Lenhart, S., and Petrella, J.R. (2022). Optimal anti-amyloid-beta therapy for Alzheimer’s disease via a personalized mathematical model. PLoS Comput. Biol. 18: e1010481, https://doi.org/10.1371/journal.pcbi.1010481.Search in Google Scholar PubMed PubMed Central
He, K., Nie, L., Ali, T., Wang, S., Chen, X., Liu, Z., Li, W., Zhang, K., Xu, J., Liu, J., et al.. (2021). Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation. Aging Cell 20: e13514, https://doi.org/10.1111/acel.13514.Search in Google Scholar PubMed PubMed Central
Holland, K.L., C. (2023). Life expectancy and long-term outlook for Alzheimer’s disease, Available at:https://www.healthline.com/health/alzheimers/life-expectancy#fa-qs.Search in Google Scholar
Holtzman, D.M., Fagan, A.M., Mackey, B., Tenkova, T., Sartorius, L., Paul, S.M., Bales, K., Ashe, K.H., Irizarry, M.C., and Hyman, B.T. (2000). Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol. 47: 739–747, https://doi.org/10.1002/1531-8249(200006)47:6<739::aid-ana6>3.3.co;2-#.10.1002/1531-8249(200006)47:6<739::AID-ANA6>3.0.CO;2-8Search in Google Scholar
Hu, Z., Yang, J., Zhang, S., Li, M., Zuo, C., Mao, C., Zhang, Z., Tang, M., Shi, C., and Xu, Y. (2025). AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice. Neural Regen Res. 20: 253–264, https://doi.org/10.4103/nrr.nrr-d-23-01277.Search in Google Scholar
Huang, Y. and Mahley, R.W. (2014). Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol. Dis. 72: 3–12, https://doi.org/10.1016/j.nbd.2014.08.025.Search in Google Scholar
Huang, Z., Ha, G., and Petitto, J. (2014). Reversal of neuronal atrophy: role of cellular immunity in neuroplasticity and aging. J. Neurol. Disord. 2, https://doi.org/10.4172/2329-6895.1000170.Search in Google Scholar
Huang, S., Liao, X., Wu, J., Zhang, X., Li, Y., Xiang, D., and Luo, S. (2022). The Microglial membrane receptor TREM2 mediates exosome secretion to promote phagocytosis of amyloid-β by microglia. FEBS Lett. 596: 1059–1071, https://doi.org/10.1002/1873-3468.14336.Search in Google Scholar
Husna Ibrahim, N., Yahaya, M.F., Mohamed, W., Teoh, S.L., Hui, C.K., and Kumar, J. (2020). Pharmacotherapy of Alzheimer’s disease: seeking clarity in a time of uncertainty. Front. Pharmacol 11: 261, https://doi.org/10.3389/fphar.2020.00261.Search in Google Scholar
Imbimbo, B.P. and Watling, M. (2019). Investigational BACE inhibitors for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs 28: 967–975, https://doi.org/10.1080/13543784.2019.1683160.Search in Google Scholar
Iwata, N., Sekiguchi, M., Hattori, Y., Takahashi, A., Asai, M., Ji, B., Higuchi, M., Staufenbiel, M., Muramatsu, S., and Saido, T.C. (2013). Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice. Sci. Rep. 3: 1472, https://doi.org/10.1038/srep01472.Search in Google Scholar
Jackson, R.J., Keiser, M.S., Meltzer, J.C., Fykstra, D.P., Dierksmeier, S.E., Hajizadeh, S., Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., et al.. (2024). APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Mol. Ther. 32: 1373–1386, https://doi.org/10.1016/j.ymthe.2024.03.024.Search in Google Scholar
Jandus, C., Simon, H.U., and von Gunten, S. (2011). Targeting siglecs--a novel pharmacological strategy for immuno- and glycotherapy. Biochem. Pharmacol. 82: 323–332, https://doi.org/10.1016/j.bcp.2011.05.018.Search in Google Scholar PubMed
Jang, H., Zheng, J., and Nussinov, R. (2007). Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process. Biophys. J. 93: 1938–1949, https://doi.org/10.1529/biophysj.107.110148.Search in Google Scholar PubMed PubMed Central
Jayant, R.D., Sosa, D., Kaushik, A., Atluri, V., Vashist, A., Tomitaka, A., and Nair, M. (2016). Current status of non-viral gene therapy for CNS disorders. Expert Opin. Drug Deliv. 13: 1433–1445, https://doi.org/10.1080/17425247.2016.1188802.Search in Google Scholar PubMed PubMed Central
Jeon, S.G., Yoo, A., Chun, D.W., Hong, S.B., Chung, H., Kim, J.I., and Moon, M. (2020). The critical role of Nurr1 as a mediator and therapeutic target in Alzheimer’s disease-related pathogenesis. Aging Dis. 11: 705–724, https://doi.org/10.14336/ad.2019.0718.Search in Google Scholar
Jiang, S., Cai, G., Yang, Z., Shi, H., Zeng, H., Ye, Q., Hu, Z., and Wang, Z. (2024). Biomimetic nanovesicles as a dual gene delivery system for the synergistic gene therapy of Alzheimer’s disease. ACS Nano 18: 11753–11768, https://doi.org/10.1021/acsnano.3c13150.Search in Google Scholar PubMed
Jiao, F., Jiang, D., Li, Y., Mei, J., Wang, Q., and Li, X. (2022). Amyloidogenesis and neurotrophic dysfunction in Alzheimer’s disease: do they have a common regulating pathway? Cells 11, https://doi.org/10.3390/cells11203201.Search in Google Scholar PubMed PubMed Central
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P.V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A.I., Lah, J.J., et al.. (2013). Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368: 107–116, https://doi.org/10.1056/nejmoa1211103.Search in Google Scholar
Kabir, M.T., Uddin, M.S., Setu, J.R., Ashraf, G.M., Bin-Jumah, M.N., and Abdel-Daim, M.M. (2020). Exploring the role of PSEN mutations in the pathogenesis of Alzheimer’s disease. Neurotox Res. 38: 833–849, https://doi.org/10.1007/s12640-020-00232-x.Search in Google Scholar PubMed
Kelleher, R.J.3rd and Shen, J. (2017). Presenilin-1 mutations and Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 114: 629–631, https://doi.org/10.1073/pnas.1619574114.Search in Google Scholar PubMed PubMed Central
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al.. (2017). A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169: 1276–1290.e1217, https://doi.org/10.1016/j.cell.2017.05.018.Search in Google Scholar PubMed
Khakh, B.S. and Deneen, B. (2019). The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 42: 187–207, https://doi.org/10.1146/annurev-neuro-070918-050443.Search in Google Scholar PubMed
Khalil, Y.A., Rabès, J.-P., Boileau, C., and Varret, M. (2021). APOE gene variants in primary dyslipidemia. Atherosclerosis 328: 11–22, https://doi.org/10.1016/j.atherosclerosis.2021.05.007.Search in Google Scholar PubMed
Kieu, C. and Look, K.A. (2023). Cost-effectiveness of a hypothetical gene therapy for Alzheimer’s disease: a markov simulation analysis. Innov Pharm. 14, https://doi.org/10.24926/iip.v14i3.5500.Search in Google Scholar PubMed PubMed Central
Kim, M., Suh, J., Romano, D., Truong, M.H., Mullin, K., Hooli, B., Norton, D., Tesco, G., Elliott, K., Wagner, S.L., et al.. (2009). Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum. Mol. Genet. 18: 3987–3996, https://doi.org/10.1093/hmg/ddp323.Search in Google Scholar PubMed PubMed Central
Kinney, J.W., Bemiller, S.M., Murtishaw, A.S., Leisgang, A.M., Salazar, A.M., and Lamb, B.T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 4: 575–590, https://doi.org/10.1016/j.trci.2018.06.014.Search in Google Scholar PubMed PubMed Central
Kins, S., Lauther, N., Szodorai, A., and Beyreuther, K. (2006). Subcellular trafficking of the amyloid precursor protein gene family and its pathogenic role in Alzheimer’s disease. Neurodegener Dis. 3: 218–226, https://doi.org/10.1159/000095259.Search in Google Scholar PubMed
Kloske, C.M., Gearon, M.D., Weekman, E.M., Rogers, C., Patel, E., Bachstetter, A., Nelson, P.T., and Wilcock, D.M. (2023). Association between APOE genotype and microglial cell morphology. J. Neuropathol. Exp. Neurol. 82: 620–630, https://doi.org/10.1093/jnen/nlad031.Search in Google Scholar PubMed PubMed Central
Knopman, D.S., Amieva, H., Petersen, R.C., Chételat, G., Holtzman, D.M., Hyman, B.T., Nixon, R.A., and Jones, D.T. (2021). Alzheimer disease. Nat. Rev. Dis. Primers 7: 33, https://doi.org/10.1038/s41572-021-00269-y.Search in Google Scholar PubMed PubMed Central
Konstantinidis, E., Molisak, A., Perrin, F., Streubel-Gallasch, L., Fayad, S., Kim, D.Y., Petri, K., Aryee, M.J., Aguilar, X., György, B., et al.. (2022). CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer’s disease PSEN 1 M146L mutation. Mol. Ther. Nucleic Acids 28: 450–461, https://doi.org/10.1016/j.omtn.2022.03.022.Search in Google Scholar PubMed PubMed Central
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al.. (2017). The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47: 566–581.e569, https://doi.org/10.1016/j.immuni.2017.08.008.Search in Google Scholar PubMed PubMed Central
Kullmann, D.M. and Lamsa, K.P. (2007). Long-term synaptic plasticity in hippocampal interneurons. Nat. Rev. Neurosci. 8: 687–699, https://doi.org/10.1038/nrn2207.Search in Google Scholar PubMed
Kumar, S.R., Markusic, D.M., Biswas, M., High, K.A., and Herzog, R.W. (2016). Clinical development of gene therapy: results and lessons from recent successes. Mol. Ther. Methods Clin. Dev. 3: 16034, https://doi.org/10.1038/mtm.2016.34.Search in Google Scholar PubMed PubMed Central
Kumar, A., Sidhu, J., Lui, F., and Tsao, J.W. (2024). Alzheimer disease. StatPearls, Treasure Island (FL).Search in Google Scholar
Kummer, M.P., Hermes, M., Delekarte, A., Hammerschmidt, T., Kumar, S., Terwel, D., Walter, J., Pape, H.C., König, S., Roeber, S., et al.. (2011). Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71: 833–844, https://doi.org/10.1016/j.neuron.2011.07.001.Search in Google Scholar PubMed
Kuszczyk, M.A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A.A., Sullivan, P.M., Holtzman, D.M., and Sadowski, M.J. (2013). Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am. J. Pathol. 182: 1750–1768, https://doi.org/10.1016/j.ajpath.2013.01.034.Search in Google Scholar PubMed PubMed Central
Lacosta, A.M., Pascual-Lucas, M., Pesini, P., Casabona, D., Pérez-Grijalba, V., Marcos-Campos, I., Sarasa, L., Canudas, J., Badi, H., Monleón, I., et al.. (2018). Safety, tolerability and immunogenicity of an active anti-Aβ(40) vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res. Ther. 10: 12, https://doi.org/10.1186/s13195-018-0340-8.Search in Google Scholar PubMed PubMed Central
Lal, R., Lin, H., and Quist, A.P. (2007). Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. Biochim. Biophys. Acta 1768: 1966–1975, https://doi.org/10.1016/j.bbamem.2007.04.021.Search in Google Scholar PubMed PubMed Central
Lee, C.Y. and Landreth, G.E. (2010). The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 117: 949–960, https://doi.org/10.1007/s00702-010-0433-4.Search in Google Scholar PubMed PubMed Central
Li, K., Li, J., Zheng, J., and Qin, S. (2019). Reactive astrocytes in neurodegenerative diseases. Aging Dis. 10: 664–675, https://doi.org/10.14336/ad.2018.0720.Search in Google Scholar PubMed PubMed Central
Li, H., Sun, B., Huang, Y., Zhang, J., Xu, X., Shen, Y., Chen, Z., Yang, J., Shen, L., Hu, Y., et al.. (2022). Gene therapy of yeast NDI1 on mitochondrial complex I dysfunction in rotenone-induced Parkinson’s disease models in vitro and vivo. Mol. Med. 28: 29, https://doi.org/10.1186/s10020-022-00456-x.Search in Google Scholar PubMed PubMed Central
Li, H., Chen, Z., Shen, Y., Xiong, T., Chen, A., Chen, L., Ye, Y., Jiang, Q., Zhang, Y., Sun, J., et al.. (2024a). Gene therapy in Aβ-induced cell and mouse models of Alzheimer’s disease through compensating defective mitochondrial complex I function. J. Transl. Med. 22: 760, https://doi.org/10.1186/s12967-024-05571-3.Search in Google Scholar PubMed PubMed Central
Li, Y.B., Fu, Q., Guo, M., Du, Y., Chen, Y., and Cheng, Y. (2024b). MicroRNAs: pioneering regulators in Alzheimer’s disease pathogenesis, diagnosis, and therapy. Transl. Psychiatry 14: 367, https://doi.org/10.1038/s41398-024-03075-8.Search in Google Scholar PubMed PubMed Central
Liao, Y.F., Wang, B.J., Cheng, H.T., Kuo, L.H., and Wolfe, M.S. (2004). Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J. Biol. Chem. 279: 49523–49532, https://doi.org/10.1074/jbc.m402034200.Search in Google Scholar
Liao, F., Jiang, H., Srivatsan, S., Xiao, Q., Lefton, K.B., Yamada, K., Mahan, T.E., Lee, J.M., Shaw, A.S., and Holtzman, D.M. (2015). Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model. Mol. Neurodegener 10: 12, https://doi.org/10.1186/s13024-015-0006-y.Search in Google Scholar PubMed PubMed Central
Liddelow, S.A., Guttenplan, K.A., Clarke, L.E., Bennett, F.C., Bohlen, C.J., Schirmer, L., Bennett, M.L., Münch, A.E., Chung, W.S., Peterson, T.C., et al.. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481–487, https://doi.org/10.1038/nature21029.Search in Google Scholar PubMed PubMed Central
Liefhebber, J.M., Martier, R., Van der Zon, T., Keskin, S., Huseinovic, A., Lubelski, J., Blits, B., Petry, H., and Konstantinova, P. (2019). In-depth characterization of a mifepristone-regulated expression system for AAV5-mediated gene therapy in the liver. Mol. Ther. Methods Clin. Dev. 13: 512–525, https://doi.org/10.1016/j.omtm.2019.05.002.Search in Google Scholar PubMed PubMed Central
Liu, Y., Studzinski, C., Beckett, T., Guan, H., Hersh, M.A., Murphy, M.P., Klein, R., and Hersh, L.B. (2009). Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease. Mol. Ther. 17: 1381–1386, https://doi.org/10.1038/mt.2009.115.Search in Google Scholar PubMed PubMed Central
Liu, C.C., Liu, C.C., Kanekiyo, T., Xu, H., and Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9: 106–118, https://doi.org/10.1038/nrneurol.2012.263.Search in Google Scholar PubMed PubMed Central
Lustbader, J.W., Cirilli, M., Lin, C., Xu, H.W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al.. (2004). ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304: 448–452, https://doi.org/10.1126/science.1091230.Search in Google Scholar PubMed
Ma, C., Hong, F., and Yang, S. (2022). Amyloidosis in Alzheimer’s disease: pathogeny, etiology, and related therapeutic directions. Molecules 27, https://doi.org/10.3390/molecules27041210.Search in Google Scholar PubMed PubMed Central
MacDougall, G., Brown, L.Y., Kantor, B., and Chiba-Falek, O. (2021). The path to progress preclinical studies of age-related neurodegenerative diseases: a perspective on rodent and hiPSC-derived models. Mol. Ther. 29: 949–972, https://doi.org/10.1016/j.ymthe.2021.01.001.Search in Google Scholar PubMed PubMed Central
Martier, R. and Konstantinova, P. (2020). Gene therapy for neurodegenerative diseases: slowing down the ticking clock. Front Neurosci. 14: 580179, https://doi.org/10.3389/fnins.2020.580179.Search in Google Scholar PubMed PubMed Central
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J.Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al.. (2019). Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570: 332–337, https://doi.org/10.1038/s41586-019-1195-2.Search in Google Scholar PubMed PubMed Central
Matsuzaki, K. (2007). Physicochemical interactions of amyloid beta-peptide with lipid bilayers. Biochim. Biophys. Acta 1768: 1935–1942, https://doi.org/10.1016/j.bbamem.2007.02.009.Search in Google Scholar PubMed
Merighi, S., Nigro, M., Travagli, A., and Gessi, S. (2022). Microglia and Alzheimer’s disease. Int. J. Mol. Sci. 23: 12990, https://doi.org/10.3390/ijms232112990.Search in Google Scholar PubMed PubMed Central
Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., and Heuschling, P. (2009). Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-β. J. Neuroimmunol. 210: 3–12, https://doi.org/10.1016/j.jneuroim.2009.02.003.Search in Google Scholar PubMed
Misra, S. (2013). Human gene therapy: a brief overview of the genetic revolution. J. Assoc. Physicians India 61: 127–133.Search in Google Scholar
Mitra, S., Behbahani, H., and Eriksdotter, M. (2019). Innovative therapy for Alzheimer’s disease-with focus on biodelivery of NGF. Front Neurosci. 13: 38, https://doi.org/10.3389/fnins.2019.00038.Search in Google Scholar PubMed PubMed Central
Montenegro, P., Chen, P., Kang, J., Lee, S.H., Leone, S., and Shen, J. (2023). Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice. Proc. Natl. Acad. Sci. U. S. A. 120, https://doi.org/10.1073/pnas.2306714120.Search in Google Scholar PubMed PubMed Central
Mookherjee, P., Green, P.S., Watson, G.S., Marques, M.A., Tanaka, K., Meeker, K.D., Meabon, J.S., Li, N., Zhu, P., Olson, V.G., et al.. (2011). GLT-1 loss accelerates cognitive deficit onset in an Alzheimer’s disease animal model. J. Alzheimers Dis. 26: 447–455, https://doi.org/10.3233/jad-2011-110503.Search in Google Scholar PubMed PubMed Central
Morille, M., Passirani, C., Vonarbourg, A., Clavreul, A., and Benoit, J.P. (2008). Progress in developing cationic vectors for non-viral systemic gene therapy against cancer. Biomaterials 29: 3477–3496, https://doi.org/10.1016/j.biomaterials.2008.04.036.Search in Google Scholar PubMed
Morroni, F. and Caccamo, A. (2024). Advances and challenges in gene therapy for Alzheimer’s disease. J. Alzheimers Dis. 101: S417–s431, https://doi.org/10.3233/jad-230783.Search in Google Scholar
Mossmann, D., Vögtle, F.N., Taskin, A.A., Teixeira, P.F., Ring, J., Burkhart, J.M., Burger, N., Pinho, C.M., Tadic, J., Loreth, D., et al.. (2014). Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 20: 662–669, https://doi.org/10.1016/j.cmet.2014.07.024.Search in Google Scholar PubMed
Müller, U.C., Deller, T., and Korte, M. (2017). Not just amyloid: physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 18: 281–298, https://doi.org/10.1038/nrn.2017.29.Search in Google Scholar PubMed
Musardo, S., Therin, S., Pelucchi, S., D’Andrea, L., Stringhi, R., Ribeiro, A., Manca, A., Balducci, C., Pagano, J., Sala, C., et al.. (2022). The development of ADAM10 endocytosis inhibitors for the treatment of Alzheimer’s disease. Mol. Ther. 30: 2474–2490, https://doi.org/10.1016/j.ymthe.2022.03.024.Search in Google Scholar PubMed PubMed Central
Nanclares, C., Baraibar, A.M., Araque, A., and Kofuji, P. (2021). Dysregulation of astrocyte-neuronal communication in Alzheimer’s disease. Int. J. Mol. Sci. 22, https://doi.org/10.3390/ijms22157887.Search in Google Scholar PubMed PubMed Central
Navarrete, M. and Araque, A. (2014). The Cajal school and the physiological role of astrocytes: a way of thinking. Front Neuroanat. 8: 33, https://doi.org/10.3389/fnana.2014.00033.Search in Google Scholar PubMed PubMed Central
Neuner, S.M., Heuer, S.E., Huentelman, M.J., O’Connell, K.M.S., and Kaczorowski, C.C. (2019). Harnessing genetic complexity to enhance translatability of Alzheimer’s disease mouse models: a path toward precision medicine. Neuron 101: 399–411.e395, https://doi.org/10.1016/j.neuron.2018.11.040.Search in Google Scholar PubMed PubMed Central
Neuner, S.M., Tcw, J., and Goate, A.M. (2020). Genetic architecture of Alzheimer’s disease. Neurobiol. Dis. 143: 104976, https://doi.org/10.1016/j.nbd.2020.104976.Search in Google Scholar PubMed PubMed Central
Ng, R.C., Cheng, O.Y., Jian, M., Kwan, J.S., Ho, P.W., Cheng, K.K., Yeung, P.K., Zhou, L.L., Hoo, R.L., Chung, S.K., et al.. (2016). Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol. Neurodegener 11: 71, https://doi.org/10.1186/s13024-016-0136-x.Search in Google Scholar PubMed PubMed Central
Ng, R.C.L., Jian, M., Yick, L.W., Bunting, M., Kwan, J.S.C., Chung, S.K., and Chan, K.H. (2020). Adiponectin gene therapy for Alzheimer disease in a mouse model: abridged secondary publication. Hong Kong Med. J. 26 (Suppl 8): 27–33.Search in Google Scholar
Ng, R.C., Jian, M., Ma, O.K., Xiang, A.W., Bunting, M., Kwan, J.S., Wong, C.W., Yick, L.W., Chung, S.K., Lam, K.S., et al.. (2024). Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease. J. Neuroinflammation 21: 77, https://doi.org/10.1186/s12974-024-03066-y.Search in Google Scholar PubMed PubMed Central
Nguyen, K.V. (2019). β-Amyloid precursor protein (APP) and the human diseases. AIMS Neurosci. 6: 273–281, https://doi.org/10.3934/Neuroscience.2019.4.273.Search in Google Scholar PubMed PubMed Central
Nguyen, T.T., Nguyen, T.T.D., Nguyen, T.K.O., Vo, T.K., and Vo, V.G. (2021). Advances in developing therapeutic strategies for Alzheimer’s disease. Biomed. Pharmacother. 139: 111623, https://doi.org/10.1016/j.biopha.2021.111623.Search in Google Scholar PubMed
Nickerson, D.A., Taylor, S.L., Fullerton, S.M., Weiss, K.M., Clark, A.G., Stengård, J.H., Salomaa, V., Boerwinkle, E., and Sing, C.F. (2000). Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res. 10: 1532–1545, https://doi.org/10.1101/gr.146900.Search in Google Scholar PubMed PubMed Central
Oishi, A., Gbahou, F., and Jockers, R. (2021). Melatonin receptors, brain functions, and therapies. Handb. Clin. Neurol. 179: 345–356, https://doi.org/10.1016/b978-0-12-819975-6.00022-4.Search in Google Scholar
Ooi, L., Dottori, M., Cook, A.L., Engel, M., Gautam, V., Grubman, A., Hernández, D., King, A.E., Maksour, S., Targa Dias Anastacio, H., et al.. (2020). If human brain organoids are the answer to understanding dementia, what are the questions? Neuroscientist 26: 438–454, https://doi.org/10.1177/1073858420912404.Search in Google Scholar PubMed PubMed Central
Ortiz-Virumbrales, M., Moreno, C.L., Kruglikov, I., Marazuela, P., Sproul, A., Jacob, S., Zimmer, M., Paull, D., Zhang, B., Schadt, E.E., et al.. (2017). CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 (N141I) neurons. Acta Neuropathol. Commun. 5: 77, https://doi.org/10.1186/s40478-017-0475-z.Search in Google Scholar PubMed PubMed Central
Owens, L.V., Benedetto, A., Dawson, N., Gaffney, C.J., and Parkin, E.T. (2021). Gene therapy-mediated enhancement of protective protein expression for the treatment of Alzheimer’s disease. Brain Res. 1753: 147264, https://doi.org/10.1016/j.brainres.2020.147264.Search in Google Scholar PubMed
Pantelidis, P., Lambert-Hammill, M., and Wierzbicki, A.S. (2003). Simple sequence-specific-primer-PCR method to identify the three main apolipoprotein E haplotypes. Clin. Chem. 49: 1945–1948, https://doi.org/10.1373/clinchem.2003.021683.Search in Google Scholar PubMed
Pardo-Moreno, T., González-Acedo, A., Rivas-Domínguez, A., García-Morales, V., García-Cozar, F.J., Ramos-Rodríguez, J.J., and Melguizo-Rodríguez, L. (2022). Therapeutic approach to Alzheimer’s disease: current treatments and new perspectives. Pharmaceutics. 14, https://doi.org/10.3390/pharmaceutics14061117.Search in Google Scholar PubMed PubMed Central
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al.. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22: 191–204, https://doi.org/10.1038/s41593-018-0296-9.Search in Google Scholar PubMed PubMed Central
Park, H. and Kim, J. (2022). Activation of melatonin receptor 1 by CRISPR-Cas9 activator ameliorates cognitive deficits in an Alzheimer’s disease mouse model. J. Pineal Res. 72: e12787, https://doi.org/10.1111/jpi.12787.Search in Google Scholar PubMed
Park, H., Oh, J., Shim, G., Cho, B., Chang, Y., Kim, S., Baek, S., Kim, H., Shin, J., Choi, H., et al.. (2019). In vivo neuronal gene editing via CRISPR-Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease. Nat. Neurosci. 22: 524–528, https://doi.org/10.1038/s41593-019-0352-0.Search in Google Scholar PubMed
Park, S.M., Kang, T.I., and So, J.S. (2021). Roles of XBP1s in transcriptional regulation of target genes. Biomedicines 9, https://doi.org/10.3390/biomedicines9070791.Search in Google Scholar PubMed PubMed Central
Parodi, J., Sepúlveda, F.J., Roa, J., Opazo, C., Inestrosa, N.C., and Aguayo, L.G. (2010). Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J. Biol. Chem. 285: 2506–2514, https://doi.org/10.1074/jbc.M109.030023.Search in Google Scholar PubMed PubMed Central
Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer’s disease: treatment strategies and their limitations. Int. J. Mol. Sci. 23, https://doi.org/10.3390/ijms232213954.Search in Google Scholar PubMed PubMed Central
Pekny, M., Pekna, M., Messing, A., Steinhäuser, C., Lee, J.M., Parpura, V., Hol, E.M., Sofroniew, M.V., and Verkhratsky, A. (2016). Astrocytes: a central element in neurological diseases. Acta Neuropathol. 131: 323–345, https://doi.org/10.1007/s00401-015-1513-1.Search in Google Scholar PubMed
Peron, R., Vatanabe, I.P., Manzine, P.R., Camins, A., and Cominetti, M.R. (2018). Alpha-secretase ADAM10 regulation: insights into Alzheimer’s disease treatment. Pharmaceuticals (Basel) 11.10.3390/ph11010012Search in Google Scholar PubMed PubMed Central
Petersen, R.C., Parisi, J.E., Dickson, D.W., Johnson, K.A., Knopman, D.S., Boeve, B.F., Jicha, G.A., Ivnik, R.J., Smith, G.E., Tangalos, E.G., et al.. (2006). Neuropathologic features of amnestic mild cognitive impairment. Arch. Neurol. 63: 665–672, https://doi.org/10.1001/archneur.63.5.665.Search in Google Scholar PubMed
Petrushina, I., Hovakimyan, A., Harahap-Carrillo, I.S., Davtyan, H., Antonyan, T., Chailyan, G., Kazarian, K., Antonenko, M., Jullienne, A., Hamer, M.M., et al.. (2020). Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials. Neurobiol. Dis. 139: 104823, https://doi.org/10.1016/j.nbd.2020.104823.Search in Google Scholar PubMed PubMed Central
Piguet, F., de Saint Denis, T., Audouard, E., Beccaria, K., André, A., Wurtz, G., Schatz, R., Alves, S., Sevin, C., Zerah, M., et al.. (2021). The challenge of gene therapy for neurological diseases: strategies and tools to achieve efficient delivery to the central nervous system. Hum. Gene Ther. 32: 349–374, https://doi.org/10.1089/hum.2020.105.Search in Google Scholar PubMed
Pizzo, P., Basso, E., Filadi, R., Greotti, E., Leparulo, A., Pendin, D., Redolfi, N., Rossini, M., Vajente, N., Pozzan, T., et al.. (2020). Presenilin-2 and calcium handling: molecules, organelles, cells and brain networks. Cells 9: 2166, https://doi.org/10.3390/cells9102166.Search in Google Scholar PubMed PubMed Central
Preman, P., Alfonso-Triguero, M., Alberdi, E., Verkhratsky, A., and Arranz, A.M. (2021). Astrocytes in Alzheimer’s disease: pathological significance and molecular pathways. Cells. 10, https://doi.org/10.3390/cells10030540.Search in Google Scholar PubMed PubMed Central
Puranik, N., Yadav, D., Chauhan, P.S., Kwak, M., and Jin, J.O. (2021). Exploring the role of gene therapy for neurological disorders. Curr. Gene Ther. 21: 11–22, https://doi.org/10.2174/1566523220999200917114101.Search in Google Scholar PubMed
Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., and Tang, Y. (2021). TREM2, microglia, and Alzheimer’s disease. Mech. Ageing Dev. 195: 111438, https://doi.org/10.1016/j.mad.2021.111438.Search in Google Scholar PubMed
Rafii, M.S., Tuszynski, M.H., Thomas, R.G., Barba, D., Brewer, J.B., Rissman, R.A., Siffert, J., and Aisen, P.S. (2018). Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with alzheimer disease: a randomized clinical trial. JAMA Neurol. 75: 834–841, https://doi.org/10.1001/jamaneurol.2018.0233.Search in Google Scholar PubMed PubMed Central
Ramakrishnan, V., Akram Husain, R.S., and Ahmed, S.S.S.J. (2017). PSEN1 gene polymorphisms in Caucasian Alzheimer’s disease: a meta-analysis. Clin. Chim. Acta 473: 65–70, https://doi.org/10.1016/j.cca.2017.08.016.Search in Google Scholar PubMed
Rauch, J.N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y.E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B.T., et al.. (2020). LRP1 is a master regulator of tau uptake and spread. Nature 580: 381–385, https://doi.org/10.1038/s41586-020-2156-5.Search in Google Scholar PubMed PubMed Central
Raulin, A.C., Doss, S.V., Trottier, Z.A., Ikezu, T.C., Bu, G., and Liu, C.C. (2022). ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol. Neurodegener 17: 72, https://doi.org/10.1186/s13024-022-00574-4.Search in Google Scholar PubMed PubMed Central
Ries, M. and Sastre, M. (2016). Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci. 8: 160, https://doi.org/10.3389/fnagi.2016.00160.Search in Google Scholar PubMed PubMed Central
Rodrigues, B.D.S., Kanekiyo, T., and Singh, J. (2020). Nerve growth factor gene delivery across the blood-brain barrier to reduce beta amyloid accumulation in AD mice. Mol. Pharm. 17: 2054–2063, https://doi.org/10.1021/acs.molpharmaceut.0c00218.Search in Google Scholar PubMed
Rosen, R.F., Tomidokoro, Y., Farberg, A.S., Dooyema, J., Ciliax, B., Preuss, T.M., Neubert, T.A., Ghiso, J.A., LeVine, H., and Walker, L.C. (2016). Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol. Aging 44: 185–196, https://doi.org/10.1016/j.neurobiolaging.2016.04.019.Search in Google Scholar PubMed PubMed Central
Ruetz, T.J., Pogson, A.N., Kashiwagi, C.M., Gagnon, S.D., Morton, B., Sun, E.D., Na, J., Yeo, R.W., Leeman, D.S., Morgens, D.W., et al.. (2024). CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells. Nature 634: 1150–1159, https://doi.org/10.1038/s41586-024-07972-2.Search in Google Scholar PubMed PubMed Central
Saidi, L.J., Polydoro, M., Kay, K.R., Sanchez, L., Mandelkow, E.M., Hyman, B.T., and Spires-Jones, T.L. (2015). Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes. J. Alzheimers Dis. 44: 937–947, https://doi.org/10.3233/jad-142094.Search in Google Scholar PubMed
Sayed, N., Allawadhi, P., Khurana, A., Singh, V., Navik, U., Pasumarthi, S.K., Khurana, I., Banothu, A.K., Weiskirchen, R., and Bharani, K.K. (2022). Gene therapy: comprehensive overview and therapeutic applications. Life Sci. 294: 120375, https://doi.org/10.1016/j.lfs.2022.120375.Search in Google Scholar PubMed
Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C.E., Cummings, J., and van der Flier, W.M. (2021). Alzheimer’s disease. Lancet 397: 1577–1590, https://doi.org/10.1016/s0140-6736(20)32205-4.Search in Google Scholar
Schindowski, K., Belarbi, K., and Buée, L. (2008). Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes Brain Behav 7 (Suppl 1): 43–56, https://doi.org/10.1111/j.1601-183X.2007.00378.x.Search in Google Scholar PubMed PubMed Central
Schlepckow, K., Monroe, K.M., Kleinberger, G., Cantuti-Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al.. (2020). Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12: e11227, https://doi.org/10.15252/emmm.201911227.Search in Google Scholar PubMed PubMed Central
Sehar, U., Rawat, P., Reddy, A.P., Kopel, J., and Reddy, P.H. (2022). Amyloid beta in aging and Alzheimer’s disease. Int. J. Mol. Sci. 23, https://doi.org/10.3390/ijms232112924.Search in Google Scholar PubMed PubMed Central
Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8: 595–608, https://doi.org/10.15252/emmm.201606210.Search in Google Scholar PubMed PubMed Central
Serrano-Pozo, A., Qian, J., Monsell, S.E., Betensky, R.A., and Hyman, B.T. (2015). APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol. 77: 917–929, https://doi.org/10.1002/ana.24369.Search in Google Scholar PubMed PubMed Central
Serrano-Pozo, A., Das, S., and Hyman, B.T. (2021). APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20: 68–80, https://doi.org/10.1016/s1474-4422(20)30412-9.Search in Google Scholar
Seshadri, S., Fitzpatrick, A.L., Ikram, M.A., DeStefano, A.L., Gudnason, V., Boada, M., Bis, J.C., Smith, A.V., Carassquillo, M.M., Lambert, J.C., et al.. (2010). Genome-wide analysis of genetic loci associated with Alzheimer disease. Jama 303: 1832–1840, https://doi.org/10.1001/jama.2010.574.Search in Google Scholar PubMed PubMed Central
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al.. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537: 50–56, https://doi.org/10.1038/nature19323.Search in Google Scholar PubMed
Shankar, G.M., Leissring, M.A., Adame, A., Sun, X., Spooner, E., Masliah, E., Selkoe, D.J., Lemere, C.A., and Walsh, D.M. (2009). Biochemical and immunohistochemical analysis of an Alzheimer’s disease mouse model reveals the presence of multiple cerebral Aβ assembly forms throughout life. Neurobiol. Dis. 36: 293–302, https://doi.org/10.1016/j.nbd.2009.07.021.Search in Google Scholar PubMed PubMed Central
Shen, J. and Kelleher, R.J.3rd (2007). The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl. Acad. Sci. U. S. A. 104: 403–409, https://doi.org/10.1073/pnas.0608332104.Search in Google Scholar PubMed PubMed Central
Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., Rojas, J.C., et al.. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549: 523–527, https://doi.org/10.1038/nature24016.Search in Google Scholar PubMed PubMed Central
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P.M., Remolina Serrano, J., Hoyle, R., and Holtzman, D.M. (2019). Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216: 2546–2561, https://doi.org/10.1084/jem.20190980.Search in Google Scholar PubMed PubMed Central
Shineman, D.W., Basi, G.S., Bizon, J.L., Colton, C.A., Greenberg, B.D., Hollister, B.A., Lincecum, J., Leblanc, G.G., Lee, L.B., Luo, F., et al.. (2011). Accelerating drug discovery for Alzheimer’s disease: best practices for preclinical animal studies. Alzheimers Res. Ther. 3: 28, https://doi.org/10.1186/alzrt90.Search in Google Scholar PubMed PubMed Central
Shirley, J.L., de Jong, Y.P., Terhorst, C., and Herzog, R.W. (2020). Immune responses to viral gene therapy vectors. Mol. Ther. 28: 709–722, https://doi.org/10.1016/j.ymthe.2020.01.001.Search in Google Scholar PubMed PubMed Central
Shulman, J.M., Imboywa, S., Giagtzoglou, N., Powers, M.P., Hu, Y., Devenport, D., Chipendo, P., Chibnik, L.B., Diamond, A., Perrimon, N., et al.. (2014). Functional screening in Drosophila identifies Alzheimer’s disease susceptibility genes and implicates Tau-mediated mechanisms. Hum. Mol. Genet. 23: 870–877, https://doi.org/10.1093/hmg/ddt478.Search in Google Scholar PubMed PubMed Central
Singh, A.K. and Pati, U. (2015). CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase. Aging Cell 14: 595–604, https://doi.org/10.1111/acel.12335.Search in Google Scholar PubMed PubMed Central
Singh, K., Sethi, P., Datta, S., Chaudhary, J.S., Kumar, S., Jain, D., Gupta, J.K., Kumar, S., Guru, A., and Panda, S.P. (2024). Advances in gene therapy approaches targeting neuro-inflammation in neurodegenerative diseases. Ageing Res. Rev. 98: 102321, https://doi.org/10.1016/j.arr.2024.102321.Search in Google Scholar PubMed
Sirisi, S., Sánchez-Aced, É., Belbin, O., and Lleó, A. (2024). APP dyshomeostasis in the pathogenesis of Alzheimer’s disease: implications for current drug targets. Alzheimer’s Res. Ther. 16: 144, https://doi.org/10.1186/s13195-024-01504-w.Search in Google Scholar PubMed PubMed Central
Spires-Jones, T.L. and Hyman, B.T. (2014). The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82: 756–771, https://doi.org/10.1016/j.neuron.2014.05.004.Search in Google Scholar PubMed PubMed Central
Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., and Roses, A.D. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 90: 1977–1981, https://doi.org/10.1073/pnas.90.5.1977.Search in Google Scholar PubMed PubMed Central
Stutzmann, G.E., Caccamo, A., LaFerla, F.M., and Parker, I. (2004). Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J. Neurosci. 24: 508–513, https://doi.org/10.1523/jneurosci.4386-03.2004.Search in Google Scholar PubMed PubMed Central
Suh, J., Choi, S.H., Romano, D.M., Gannon, M.A., Lesinski, A.N., Kim, D.Y., and Tanzi, R.E. (2013). ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function. Neuron 80: 385–401, https://doi.org/10.1016/j.neuron.2013.08.035.Search in Google Scholar PubMed PubMed Central
Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A.M., Koo, S.Y., Wang, L., Qiao, D., Loi, J., et al.. (2019). CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nat. Commun. 10: 53, https://doi.org/10.1038/s41467-018-07971-8.Search in Google Scholar PubMed PubMed Central
Suzuki, K., Iwata, A., and Iwatsubo, T. (2017). The past, present, and future of disease-modifying therapies for Alzheimer’s disease. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93: 757–771, https://doi.org/10.2183/pjab.93.048.Search in Google Scholar PubMed PubMed Central
Swardfager, W., Lanctôt, K., Rothenburg, L., Wong, A., Cappell, J., and Herrmann, N. (2010). A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry 68: 930–941, https://doi.org/10.1016/j.biopsych.2010.06.012.Search in Google Scholar PubMed
Tackenberg, C. and Nitsch, R.M. (2019). The secreted APP ectodomain sAPPα, but not sAPPβ, protects neurons against Aβ oligomer-induced dendritic spine loss and increased tau phosphorylation. Mol Brain 12: 27, https://doi.org/10.1186/s13041-019-0447-2.Search in Google Scholar PubMed PubMed Central
Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M., Yamaguchi, H., Sugihara, S., et al.. (1998). Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. U. S. A. 95: 9637–9641, https://doi.org/10.1073/pnas.95.16.9637.Search in Google Scholar PubMed PubMed Central
Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., Trillat, A.C., Stern, D.M., Arancio, O., and Yan, S.S. (2005). ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. Faseb J. 19: 597–598, https://doi.org/10.1096/fj.04-2582fje.Search in Google Scholar PubMed
Tao, Q.Q., Chen, Y.C., and Wu, Z.Y. (2019). The role of CD2AP in the pathogenesis of Alzheimer’s disease. Aging Dis. 10: 901–907, https://doi.org/10.14336/ad.2018.1025.Search in Google Scholar
Tateno, H., Li, H., Schur, M.J., Bovin, N., Crocker, P.R., Wakarchuk, W.W., and Paulson, J.C. (2007). Distinct endocytic mechanisms of CD22 (Siglec-2) and Siglec-F reflect roles in cell signaling and innate immunity. Mol. Cell. Biol. 27: 5699–5710, https://doi.org/10.1128/mcb.00383-07.Search in Google Scholar PubMed PubMed Central
Tedeschi, D.V., da Cunha, A.F., Cominetti, M.R., and Pedroso, R.V. (2021). Efficacy of gene therapy to restore cognition in Alzheimer’s disease: a systematic review. Curr. Gene Ther. 21: 246–257, https://doi.org/10.2174/1566523221666210120091146.Search in Google Scholar PubMed
Thal, D.R., Rüb, U., Orantes, M., and Braak, H. (2002). Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58: 1791–1800, https://doi.org/10.1212/wnl.58.12.1791.Search in Google Scholar PubMed
Thomas, M. and Klibanov, A.M. (2003). Non-viral gene therapy: polycation-mediated DNA delivery. Appl. Microbiol. Biotechnol. 62: 27–34, https://doi.org/10.1007/s00253-003-1321-8.Search in Google Scholar PubMed
Timón-Gómez, A., Nývltová, E., Abriata, L.A., Vila, A.J., Hosler, J., and Barrientos, A. (2018). Mitochondrial cytochrome c oxidase biogenesis: recent developments. Semin. Cell Dev. Biol. 76: 163–178, https://doi.org/10.1016/j.semcdb.2017.08.055.Search in Google Scholar PubMed PubMed Central
Trejo-Lopez, J.A., Yachnis, A.T., and Prokop, S. (2022). Neuropathology of Alzheimer’s disease. Neurotherapeutics 19: 173–185, https://doi.org/10.1007/s13311-021-01146-y.Search in Google Scholar PubMed PubMed Central
Tuszynski, M.H., Yang, J.H., Barba, D., U, H.S., Bakay, R.A., Pay, M.M., Masliah, E., Conner, J.M., Kobalka, P., Roy, S., et al.. (2015). Nerve growth factor gene therapy: activation of neuronal responses in alzheimer disease. JAMA Neurol. 72: 1139–1147, https://doi.org/10.1001/jamaneurol.2015.1807.Search in Google Scholar PubMed PubMed Central
Ulrich, J.D., Ulland, T.K., Mahan, T.E., Nyström, S., Nilsson, K.P., Song, W.M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al.. (2018). ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215: 1047–1058, https://doi.org/10.1084/jem.20171265.Search in Google Scholar PubMed PubMed Central
Uyemura, K., Castle, S.C., and Makinodan, T. (2002). The frail elderly: role of dendritic cells in the susceptibility of infection. Mech. Ageing Dev. 123: 955–962, https://doi.org/10.1016/s0047-6374(02)00033-7.Search in Google Scholar PubMed
Valiukas, Z., Ephraim, R., Tangalakis, K., Davidson, M., Apostolopoulos, V., and Feehan, J. (2022). Immunotherapies for Alzheimer’s disease-A review. Vaccines (Basel) 10, https://doi.org/10.3390/vaccines10091527.Search in Google Scholar PubMed PubMed Central
Vodovotz, Y., Lucia, M.S., Flanders, K.C., Chesler, L., Xie, Q.W., Smith, T.W., Weidner, J., Mumford, R., Webber, R., Nathan, C., et al.. (1996). Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J. Exp. Med. 184: 1425–1433, https://doi.org/10.1084/jem.184.4.1425.Search in Google Scholar PubMed PubMed Central
Walther, W. and Stein, U. (2000). Viral vectors for gene transfer: a review of their use in the treatment of human diseases. Drugs 60: 249–271, https://doi.org/10.2165/00003495-200060020-00002.Search in Google Scholar PubMed
Wang, D.S., Dickson, D.W., and Malter, J.S. (2006). beta-Amyloid degradation and Alzheimer’s disease. J. Biomed. Biotechnol. 2006: 58406, https://doi.org/10.1155/jbb/2006/58406.Search in Google Scholar PubMed PubMed Central
Wang, C.Y., Finstad, C.L., Walfield, A.M., Sia, C., Sokoll, K.K., Chang, T.Y., Fang, X.D., Hung, C.H., Hutter-Paier, B., and Windisch, M. (2007). Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25: 3041–3052, https://doi.org/10.1016/j.vaccine.2007.01.031.Search in Google Scholar PubMed
Wang, C., Najm, R., Xu, Q., Jeong, D.E., Walker, D., Balestra, M.E., Yoon, S.Y., Yuan, H., Li, G., Miller, Z.A., et al.. (2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24: 647–657, https://doi.org/10.1038/s41591-018-0004-z.Search in Google Scholar PubMed PubMed Central
Wang, P., Yang, P., Qian, K., Li, Y., Xu, S., Meng, R., Guo, Q., Cheng, Y., Cao, J., Xu, M., et al.. (2022). Precise gene delivery systems with detachable albumin shell remodeling dysfunctional microglia by TREM2 for treatment of Alzheimer’s disease. Biomaterials 281: 121360, https://doi.org/10.1016/j.biomaterials.2021.121360.Search in Google Scholar PubMed
Wang, Y., Wang, X., Xie, R., Burger, J.C., Tong, Y., and Gong, S. (2023). Overcoming the blood-brain barrier for gene therapy via systemic administration of GSH-responsive silica nanocapsules. Adv. Mater. 35: e2208018, https://doi.org/10.1002/adma.202208018.Search in Google Scholar PubMed
Wang, H., Shi, C., Jiang, L., Liu, X., Tang, R., and Tang, M. (2024a). Neuroimaging techniques, gene therapy, and gut microbiota: Frontier advances and integrated applications in Alzheimer’s Disease research. Front Aging Neurosci. 16: 1485657, https://doi.org/10.3389/fnagi.2024.1485657.Search in Google Scholar PubMed PubMed Central
Wang, X., Xie, Y., Fan, X., Wu, X., Wang, D., and Zhu, L. (2024b). Intermittent hypoxia training enhances Aβ endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer’s disease. Alzheimers Res. Ther. 16: 121, https://doi.org/10.1186/s13195-024-01489-6.Search in Google Scholar PubMed PubMed Central
Wei, M., Wu, T., and Chen, N. (2024). Bridging neurotrophic factors and bioactive peptides to Alzheimer’s disease. Ageing Res. Rev. 94: 102177, https://doi.org/10.1016/j.arr.2023.102177.Search in Google Scholar PubMed
Weisgraber, K.H. (1990). Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112. J. Lipid Res. 31: 1503–1511, https://doi.org/10.1016/s0022-2275(20)42621-5.Search in Google Scholar
Westermark, P., Benson, M.D., Buxbaum, J.N., Cohen, A.S., Frangione, B., Ikeda, S., Masters, C.L., Merlini, G., Saraiva, M.J., and Sipe, J.D. (2007). A primer of amyloid nomenclature. Amyloid 14: 179–183, https://doi.org/10.1080/13506120701460923.Search in Google Scholar PubMed
Wilkins, H.M. (2023). Interactions between amyloid, amyloid precursor protein, and mitochondria. Biochem. Soc. Trans. 51: 173–182, https://doi.org/10.1042/bst20220518.Search in Google Scholar PubMed PubMed Central
Winblad, B. and Machado, J.C. (2008). Use of rivastigmine transdermal patch in the treatment of Alzheimer’s disease. Expert Opin. Drug Deliv. 5: 1377–1386, https://doi.org/10.1517/17425240802542690.Search in Google Scholar PubMed
Wißfeld, J., Nozaki, I., Mathews, M., Raschka, T., Ebeling, C., Hornung, V., Brüstle, O., and Neumann, H. (2021). Deletion of Alzheimer’s disease-associated CD33 results in an inflammatory human microglia phenotype. Glia 69: 1393–1412, https://doi.org/10.1002/glia.23968.Search in Google Scholar PubMed
Wongprayoon, P. and Govitrapong, P. (2021). Melatonin receptor as a drug target for neuroprotection. Curr. Mol. Pharmacol. 14: 150–164, https://doi.org/10.2174/18744672mta17otcb0.Search in Google Scholar
Xiao, L. and Loh, Y.P. (2022). Neurotrophic factor-α1/carboxypeptidase E functions in neuroprotection and alleviates depression. Front Mol. Neurosci. 15: 918852, https://doi.org/10.3389/fnmol.2022.918852.Search in Google Scholar PubMed PubMed Central
Xiao, L., Sharma, V.K., Toulabi, L., Yang, X., Lee, C., Abebe, D., Peltekian, A., Arnaoutova, I., Lou, H., and Loh, Y.P. (2021). Neurotrophic factor-α1, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF. Transl. Psychiatry 11: 24, https://doi.org/10.1038/s41398-020-01112-w.Search in Google Scholar PubMed PubMed Central
Xiao, L., Yang, X., Sharma, V.K., Abebe, D., and Loh, Y.P. (2023). Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer’s Disease male mice. Mol. Psychiatry 28: 3332–3342, https://doi.org/10.1038/s41380-023-02135-7.Search in Google Scholar PubMed PubMed Central
Xing, Y.-q., Li, A., Yang, Y., Li, X.-x., Zhang, L.-n., and Guo, H.-c. (2018). The regulation of FOXO1 and its role in disease progression. Life Sci. 193: 124–131, https://doi.org/10.1016/j.lfs.2017.11.030.Search in Google Scholar PubMed
Yamamoto, K., Yoshida, H., Kokame, K., Kaufman, R.J., and Mori, K. (2004). Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J. Biochem. 136: 343–350, https://doi.org/10.1093/jb/mvh122.Search in Google Scholar PubMed
Yamamoto, M., Kiyota, T., Walsh, S.M., Liu, J., Kipnis, J., and Ikezu, T. (2008). Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J. Immunol. 181: 3877–3886, https://doi.org/10.4049/jimmunol.181.6.3877.Search in Google Scholar PubMed PubMed Central
Yang, Z., Kuboyama, T., and Tohda, C. (2019). Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression. Phytother Res. 33: 1114–1121, https://doi.org/10.1002/ptr.6305.Search in Google Scholar PubMed
Yang, Y., Bagyinszky, E., and An, S.S.A. (2023a). Presenilin-1 (PSEN1) mutations: clinical phenotypes beyond Alzheimer’s disease. Int. J. Mol. Sci. 24, https://doi.org/10.3390/ijms24098417.Search in Google Scholar PubMed PubMed Central
Yang, Y., Seok, M.-J., Kim, Y.E., Choi, Y., Song, J.-J., Sulistio, Y.A., Kim, S.-h., Chang, M.-Y., Oh, S.-J., Nam, M.-H., et al.. (2023b). Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology. Mol. Psychiatr. 28: 5359–5374, https://doi.org/10.1038/s41380-022-01693-6.Search in Google Scholar PubMed
Yiannopoulou, K.G. and Papageorgiou, S.G. (2013). Current and future treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 6: 19–33, https://doi.org/10.1177/1756285612461679.Search in Google Scholar PubMed PubMed Central
Yiannopoulou, K.G. and Papageorgiou, S.G. (2020). Current and future treatments in alzheimer disease: an update. J. Cent. Nerv. Syst. Dis. 12, https://doi.org/10.1177/1179573520907397.Search in Google Scholar PubMed PubMed Central
Yu, Y. and Ye, R.D. (2015). Microglial Aβ receptors in Alzheimer’s disease. Cell Mol. Neurobiol. 35: 71–83, https://doi.org/10.1007/s10571-014-0101-6.Search in Google Scholar PubMed PubMed Central
Yuan, X.Z., Sun, S., Tan, C.C., Yu, J.T., and Tan, L. (2017). The role of ADAM10 in Alzheimer’s disease. J. Alzheimers Dis. 58: 303–322, https://doi.org/10.3233/jad-170061.Search in Google Scholar
Zenaro, E., Piacentino, G., and Constantin, G. (2017). The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 107: 41–56, https://doi.org/10.1016/j.nbd.2016.07.007.Search in Google Scholar PubMed PubMed Central
Zhang, Y.W. and Xu, H. (2007). Molecular and cellular mechanisms for Alzheimer’s disease: understanding APP metabolism. Curr. Mol. Med. 7: 687–696, https://doi.org/10.2174/156652407782564462.Search in Google Scholar PubMed
Zhang, Y., Chen, H., Li, R., Sterling, K., and Song, W. (2023). Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct. Targeted Ther. 8: 248, https://doi.org/10.1038/s41392-023-01484-7.Search in Google Scholar PubMed PubMed Central
Zhao, L., Gottesdiener, A.J., Parmar, M., Li, M., Kaminsky, S.M., Chiuchiolo, M.J., Sondhi, D., Sullivan, P.M., Holtzman, D.M., Crystal, R.G., et al.. (2016). Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer’s disease mouse models. Neurobiol. Aging 44: 159–172, https://doi.org/10.1016/j.neurobiolaging.2016.04.020.Search in Google Scholar PubMed
Zhao, Y., Wu, X., Li, X., Jiang, L.L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J.C., Zhang, M., et al.. (2018). TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97: 1023–1031.e1027, https://doi.org/10.1016/j.neuron.2018.01.031.Search in Google Scholar PubMed PubMed Central
Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L.M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., et al.. (2020). Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron 106: 727–742.e726, https://doi.org/10.1016/j.neuron.2020.02.034.Search in Google Scholar PubMed PubMed Central
© 2025 Walter de Gruyter GmbH, Berlin/Boston