Volume 3, Issue 4

As a neurodegenerative disorder, Alzheimer disease (AD) is the most common form of dementia found in the aging population. Immunotherapy with passive or active immunizations targeting amyloid beta (Aβ) build-up in the brain may provide a possible treatment option and may help prevent AD from progressing. A number of passive immunizations with anti-Aβ42 antibodies are in different phases of clinical trials. One active immunization approach, AN-1792, was stopped after the development of autoimmune encephalitis in 6% of patients and a second one, CAD106, in which a small Aβ epitope is used, is currently in safety and tolerability studies. Besides active immunizations with proteins or peptides, active immunizations using DNA which codes for the protein against which the immune response will be directed, so called genetic immunizations, provide additional safety as the immune response in DNA immunizations differs quantitatively and qualitatively from the response elicited by peptide immunizations. We summarize in this review our data using DNA Aβ42 immunizations in mouse models and discuss the results together with the results presented by many other groups working on a DNA vaccine as treatment option for AD.

The challenge with controlling the differentiation of human pluripotent cells to generate functional dopaminergic neurons for the treatment of Parkinson’s disease has undergone significant progress in recent years. Here, we summarize the differences between newer and older protocols for generating midbrain dopaminergic neurons from human pluripotent stem cells, and we highlight the importance of following developmental pathways during differentiation. The field has now developed to a point where it is timely to take human pluripotent stem cells one step closer to clinical use, and cell criteria to be fulfilled for such developments are outlined in this review.

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

The name astroglia unifies many non-excitable neural cells that act as primary homeostatic cells in the nervous system. Neuronal activity triggers multiple homeostatic responses of astroglia that include increase in metabolic activity and synthesis of neuronal preferred energy substrate lactate, clearance of neurotransmitters and buffering of extracellular K+ ions to name but a few. Many (if not all) of astroglial homeostatic responses are controlled by dynamic changes in the cytoplasmic concentration of two cations, Ca2+ and Na+. Intracellular concentration of these ions is tightly controlled by several transporters and can be rapidly affected by the activation of respective fluxes through ionic channels or ion exchangers. Here, we provide a comprehensive review of astroglial Ca2+ and Na+ signalling.

Despite 50 years of pharmacological and psychosocial interventions schizophrenia remains one of the leading causes of disability. The inability to function in everyday settings includes deficits in performance of social, occupational, and independent living activities. Schizophrenia is also a life-shortening illness, caused mainly by poor physical health and its complications. Dysfunctional lifestyles including sedentary behavior and lack of physical activity prevail, while treatment with adipogenic antipsychotic medication interacts with poor performance in screening, monitoring, and intervention that result in shortening of life expectancies by 25–30 years. Disability interferes with self-care and medical care, further worsening physical health to produce a vicious cycle of disability. Further, the neurobiological impact of obesity on brain functioning is substantial and relevant to schizophrenia. Decision making deficits that lead to choices resulting in obesity themselves have neurobiological determinants. Simultaneous treatment of cognitive deficits and related deficits in functional skills, ubiquitous determinants of everyday functioning in schizophrenia, and targeted interventions aimed at poor physical health, especially obesity and associated comorbidities, may lead to additive or even interactive gains in everyday functioning in patients with schizophrenia not previously realized with other interventions.

Gene products such as organelles, proteins and RNAs are actively transported to synaptic terminals for the remodeling of pre-existing neuronal connections and formation of new ones. Proteins described as molecular motors mediate this transport and utilize specialized cytoskeletal proteins that function as molecular tracks for the motor based transport of cargos. Molecular motors such as kinesins and dynein’s move along microtubule tracks formed by tubulins whereas myosin motors utilize tracks formed by actin. Deficits in active transport of gene products have been implicated in a number of neurological disorders. We describe such disorders collectively as “transportopathies”. Here we review current knowledge of critical components of active transport and their relevance to neurodegenerative diseases.

Current therapies for immune-mediated inflammatory disorders in peripheral nerves are non-specific, and partly efficacious. Peripheral nerve regeneration following axonal degeneration or injury is suboptimal, with current therapies focused on modulating the underlying etiology and treating the consequences, such as neuropathic pain and weakness. Despite significant advances in understanding mechanisms of peripheral nerve inflammation, as well as axonal degeneration and regeneration, there has been limited translation into effective new drugs for these disorders. A major limitation in the field has been the unavailability of reliable disease models or research tools that mimic some key essential features of these human conditions. A relatively overlooked aspect of peripheral nerve regeneration has been neurovascular repair required to restore the homeostatic microenvironment necessary for normal function. Using Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as examples of human acute and chronic immune-mediated peripheral neuroinflammatory disorders respectively, we have performed detailed studies in representative mouse models to demonstrate essential features of the human disorders. These models are important tools to develop and test treatment strategies using realistic outcomes measures applicable to affected patients. In vitro models of the human blood-nerve barrier using endothelial cells derived by endoneurial microvessels provide insights into pro-inflammatory leukocyte-endothelial cell interactions relevant to peripheral neuroinflammation, as well as potential mediators and signaling pathways required for vascular proliferation, angiogenesis, remodeling and tight junction specialization necessary to restore peripheral nerve function following injury. This review discusses some of the progress being made in translational peripheral neurobiology and some future

A growing body of research deals with the relationship between the endosomal and autophagic/lysosomal pathways during developmental stages of the central nervous system. This includes their possible influence regarding the onset and progression of specific neurodegenerative disorders. In this review we focus our attention on major alterations affecting two organelles: autophagosomes and multivesicular bodies, both of which are located at the intersection point of their respective pathways.

Schizophrenia is a disorder characterized by a variety of symptoms, which among others include hallucinations, delusions and passivity experiences. It has been found that individuals with schizophrenia misattribute their own thoughts and actions to an outside agency (source monitoring deficits), which could account for psychotic experiences such as that of hearing voices. In order to explain the source-monitoring deficits as well as psychosis, it has been proposed that mechanisms that enable anticipation and recognition of sensory consequences of one’s own actions are impaired in schizophrenia. Importantly, such mechanisms may require accurate cortical sensory representations such as in the primary somatosensory cortex (S1). The establishment and maintenance of cortical sensory representations has been found to utilize a sleep-related brain rhythm known as spindling. Namely, in the perinatal period in humans and animals, and possibly also thereafter, spontaneous activity in the sensory periphery drives spindle activity in the developing cortical sensory areas, which then contributes to the formation of sensory representations that match bodily features. For example, muscle twitch-spindle sequences during sleep facilitate the formation and maintenance of S1 in accordance with the layout of musculature. This process has been proposed to continue throughout the lifespan and may be particularly important during periods of bodily changes (adolescence, menopause). In schizophrenia, the amount of sleep spindle activity is markedly reduced, which would be expected to result in insufficient cortical sensory representations and have relevance for the relative inability of individuals with schizophrenia to accurately recognize self-initiated actions.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a multisystem, autosomal recessive disorder characterized by ptosis, progressive external ophthalmoplegia, gastroparesis cachexia, peripheral neuropathy, and diffuse leukoencephalopathy. MNGIE is rare and the prevalence is unknown, however, to date there have been 76 mutations reported in the TYMP gene associated with MNGIE. We report two novel mutations that have not been previously described in a patient with clinical MNGIE syndrome.