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Alzheimer’s disease (AD) is an age-related dementia, with the pathological hallmarks of neuritic plaques and neurofibrillary tangles, brain atrophy and loss of synaptic terminals. Dysfunctional mitochondrial bioenergetics is implicated as a contributing factor to the cognitive decline observed in AD. We hypothesized that, in the presence of the AD neurotoxic peptide beta-amyloid, mitochondrial respiration is impaired early in synaptic terminals, which are vital to cognitive performance, preferentially in cognitive centers of the brain. We compared oxygen consumption in synaptosomal and perikaryal mitochondria prepared from the cerebral cortex and cerebellum of wild type (WT) and AD transgenic Tg2576 mice. Compared to WT mice, Tg2576 mice showed decreased mitochondrial respiration in the cerebral cortex specifically in synaptosomal fraction, while the perikaryal mitochondria were unaffected. Neither mitochondrial fraction was affected in the cerebellum of Tg2576 mice as compared to WT. The occurrence of a bioenergetic defect in synaptic terminals of mice overexpressing mutant beta-amyloid, in particular in an area of the brain important to cognition, points to an early role of mitochondrial defects in the onset of cognitive deficits in AD.

Both Erythropoietin (EPO) and bone marrow stromal cells (BMSCs) have been shown to improve outcome after stroke. EPO may improve outcome after stroke through its actions on blood progenitor cells, angiogenesis, or direct action in the CNS. BMSCs may improve outcome after stroke by regeneration, altering plasticity of viable cells, or prevention of cell death. Sorting out these potential modes of actions for EPO and BMSCs has been difficult using in vivo models of stroke. This study investigated neuroprotection afforded by EPO, BMSCs and the combination of these modalities in mouse hippocampal slice cultures after oxygen glucose deprivation (OGD). Significant neuroprotection was observed following post-injury treatment of slice cultures with BMSCs and neuroprotection was augmented by treating BMSCs with EPO. EPO alone did not protect neurons from OGD when given after injury, but was effective when given prior to OGD. The failure of EPO to protect when given after injury did not appear to result from its inability to activate EPO signaling pathways involving phosphorylation of Akt. This study supports the implication that BMSCs may rescue dying neurons after ischemia by providing trophic support. The data also show that EPO’s actions as a neuroprotective agent following stroke may be mediated by its actions on BMSCs.

The novel anti-epileptic drug lacosamide targets two proteins — voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP-2) — suggesting dual modes of action for lacosamide. We recently identified the neurite outgrowth and axonal guidance protein CRMP-2 as a novel partner and regulator of the presynaptic N-type voltage-gated Ca2+ channel (CaV2.2) [Brittain et al., J. Biol. Chem. 284: 31375–31390 (2009)]. Here we examined the effects of lacosamide on voltage-gated Ba2+ channels. Lacosamide did not affect Ba2+ currents via N- and P/Q- channels in rat hippocampal neurons or L-type Ca2+ channels in a mouse CNS neuronal cell line, respectively. N-type Ba2+ currents, augmented by CRMP-2 expression, were also unaffected by acute or chronic lacosamide exposure. These results establish that the anti-epileptic mode of action of lacosamide does not involve these voltage-gated Ca2+ channels.

Neuropathological and biochemical studies in a case of Gerstmann-Straüssler-Scheinker disease bearing the PRNP P102L-129V mutation showed numerous multicentric PrPres in the cerebral cortex, striatum, thalamus and cerebellum, PrPres globular deposits in the anterior and posterior horns of the spinal cord, and multiple granular PrPres deposits in the grey and white matter of the encephalon and spinal cord. Western blots with antiPrPres antibodies revealed several weak bands ranging from 36 to 66 kDa, weak bands of 29 and 24 kDa, a strong band of about 20 kDa, a low band of molecular weight around 15 kDa and a weaker band of about 7 kDa. Spongiform degeneration was absent. Hyper-phosphorylated 3R and 4R tau occurred in dystrophic neurites surrounding PrPres plaques, neuropil threads and, to a lesser degree, in the form of neurofibrillary tangles. Gel electrophoresis of sarkosyl-insoluble fractions and western blotting with anti-phospho-tau antibodies showed a pattern similar to that seen in Alzheimer disease cases run in parallel. Dystrophic neurites in the vicinity of PrPres plaques were enriched in voltage dependent anion channel thus suggesting abnormal accumulation of mitochondria. These changes were associated with increased oxidative damage in neurons and astrocytes, Finally, increased expression of active stress kinases, that have the capacity to phosphorylate tau in vitro, p38 (p-38-P) and SAPK/ JNK (SAPK/JNK-P) was found in cell processes surrounding PrP plaques. Together, these observations provide evidences of mitochondrial abnormalities, and increased oxidative stress damage and oxidative stress responses in GSS bearing the PRNP P102L-129V mutation.

One of the most remarkable observations in developmental neuroscience is the plasticity of the developing brain. Although recent findings suggest that the developing brain possesses substantial compensatory potential, the mechanisms of reorganization and its limitations remain largely unknown. This review includes studies elucidating the complexities of brain reorganization in response to early brain injury. It describes the factors influencing the pattern and degree of brain plasticity, provides insight into the patterns of reorganization in different brain systems and offers guidelines for clinicians in the field of neurorehabilitation. This knowledge is crucial in clinical work when designing the appropriate type and timing of interventions for children with early brain injuries

Human neurospheres are free-floating spherical clusters generated from a single neural stem cell and comprising cells at different stages of maturation in the neuronal and glial lineages. Although recent findings have disproved the original idea of clonally derived neurospheres according to the paradigm of one stem cell — one neurosphere, they still represent a valid model for growing neural stem cell cultures in vitro. While the immunocytochemical approach to the identification of stem cells, progenitor cells, and mature cells has been extensively used, scant data are available about the ultrastructural arrangement of different cell types within the neurosphere. This paper provides, by means of scanning electron microscopy, some new insights into the three-dimensional assembly of human neurospheres, trying to correlate some parameters such as cell density, shape and growing strategies with the immunolocalization of some antigens such as nestin, GFAP, α-internexin and βIII-tubulin. The major findings from this study are: a) regardless of the stage of in vitro maturation, the growth of the spheres is the result of mitotic divisions producing the aspect of an irregular budding mechanism in the outermost layer look like; b) analysis of the volumetric composition of the inner core has revealed the presence of two alternative shape pattern (pyramidal vs rounded cells) possibly related to both the ongoing maturation stages and GFAP and internexin expression.

In neuronal circuits, excitatory synaptic transmission predominantly occurs at postsynaptic protrusions called dendritic spines. Spines are highly plastic structures capable of formation, enlargement, shrinkage, and elimination over time. Individual spine morphology is widely variable, and evidence suggests these differences in morphology are relevant to spine function. Recent reports provide evidence that spine structural plasticity underlies functional synaptic changes, including those seen in animal models of learning and memory plasticity. Conversely, impairments in cognitive functions, such as those commonly seen in aging, have recently been linked to and correlated with alterations in spine density and morphology. In addition, dendritic spine density and morphology also appear to be altered in various transgenic animal models of neurodegenerative diseases. Ultimately, an understanding of the synaptic basis of age- and disease-related cognitive impairments may lead to the development of drug treatments that can restore or protect synaptic profiles in neural circuits that mediate cognition.

Alzheimer’s disease (AD) is the most frequent cause of dementia in the elderly, characterized by the presence of cerebral amyloid plaques and neurofibrillary tangles. The causes of the disease are not well understood, especially considering that more than 95% of AD patients are non-familial. Due to the similarity of brain regions affected in herpes simplex encephalitis to those mainly affected in AD, and owing to the very high prevalence of latent herpes simplex virus type 1 (HSV1) infection, reactivation of HSV1 was proposed as one of the possible causes of AD. The trigeminal ganglion, located only a few millimeters from the entorhinal cortex, is the primary site of HSV1 latency, although other sites including the sensory neurons, the nodose ganglion of the vagus nerve and other regions of the brain may be involved, possibly in relation to very early neurofibrillary AD changes in the dorsal raphe, locus coeruleus and other brainstem nuclei. Novel data obtained upon infection of cultured neuronal cells and mouse brain with HSV1 further show that HSV1 infection causes intracellular amyloid-beta protein accumulation, as well as abnormal phosphorylation of tau protein, the major component of tangles. Another interesting fact is the existence of a significant degree of homology between HSV1 components and AD susceptibility genes. In this review we summarize findings that reveal connections between the two conditions, as well as different suggestions for the mechanisms of HSV1-induced AD. As most of the available results support a connection of AD and HSV1 infection, antiviral therapy should be taken into consideration for AD treatment following early diagnosis.

The possibility of identifying novel biomarkers for neurodegenerative diseases has been greatly enhanced with recent advances in genomics and proteomics. Novel technologies have the potential to hasten the development of new biomarkers useful as predictors of disease etiology and outcome, as well as responsiveness to therapy. Disease-modifying new therapies are very much needed in modern approaches to treatment of neurodegenerative diseases. Current progress in the field encounters a degree of skepticism about the reliability of genomic and proteomic data and its relevance for clinical applications. Standard operating procedures covering sample collection, methodology and statistical analysis need to be fully developed and strictly adhered to in order to assure reproducible and clinically relevant results. Previous studies involving patients with neurodegenerative diseases show promise in using genomic and proteomic approaches for development of new biomarkers. Confirmation of any novel biomarker in multiple independent patient cohorts and correlation of the improvement in biomarker endpoint with clinical improvement in longitudinal patient studies remains crucial for future successful application. We propose that a combination of approaches in biomarker discovery may in the end lead to identification of promising candidates at DNA, RNA, protein and small molecule level.

Lipidized tumours of the central nervous system are very rare. Lipidization of tumour cells is a histological hallmark of pleomorphic xanthoastrocytoma and cerebellar neurolipocytoma and has been described in some other primary neuroepithelial tumours such as glioblastoma, cerebral primitive neuroectodermal tumour, central neurocytoma and ependymoma. However, a few cases of lipidized low-grade glial tumours that could not be classified to the fore mentioned categories have been reported, as well. We report a new case of such a tumour occupying the right temporal lobe in a 23-year old woman. Histologically, the tumour was composed of GFAP positive glial cells with areas of complete cell lipidization. More than a two years after the surgery, the patient is well and asymptomatic supporting presumed favourable clinical course of these rare tumours. The recommended treatment plan for these presumably benignant tumours should be continued with radiographic surveillance after the gross total resection.

The aim of this paper is to provide translation of probably the first report (Studnička 1894) demonstrating that the telencephalon of all vertebrate taxa (including fishes and amphibians) is characterized by the presence of the cerebral cortex (pallium). This report was one of those initiating a century-long and still not fully resolved discussion concerning homologies of various pallial subdivisions in different vertebrate taxa and probably the first to draw attention to the importance of careful study of the pallium in representatives of agnathans (Cyclostomes) such as lampreys (Petromyzonts) and hagfishes (Myxinoids). This article also briefly reviews the current status of comparative research on vertebrate telencephalon, and provides historical notes which position Studnička’s report in its historical context.