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Amyloid plaques, the hallmark of Alzheimer’s disease (AD), contain fibrillar β-amyloid (Aβ) 1-40 and 1-42 peptides. Herpes simplex virus 1 (HSV-1) has been implicated as a risk factor for AD and found to co-localize within amyloid plaques. Aβ 1-40 and Aβ 1-42 display anti-bacterial, anti-yeast and anti-viral activities. Here, fibroblast, epithelial and neuronal cell lines were exposed to Aβ 1-40 or Aβ 1-42 and challenged with HSV-1. Quantitative analysis revealed that Aβ 1-40 and Aβ 1-42 inhibited HSV-1 replication when added 2 h prior to or concomitantly with virus challenge, but not when added 2 or 6 h after virus addition. In contrast, Aβ 1-40 and Aβ 1-42 did not prevent replication of the non-enveloped human adenovirus. In comparison, antimicrobial peptide LL-37 prevented HSV-1 infection independently of its sequence of addition. Our findings showed also that Aβ 1-40 and Aβ 1-42 acted directly on HSV-1 in a cell-free system and prevented viral entry into cells. The sequence homology between Aβ and a proximal transmembrane region of HSV-1 glycoprotein B suggested that Aβ interference with HSV-1 replication could involve its insertion into the HSV-1 envelope. Our data suggest that Aβ peptides represent a novel class of antimicrobial peptides that protect against neurotropic enveloped virus infections such as HSV-1. Overproduction of Aβ peptide to protect against latent herpes viruses and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of AD.

The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (1H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla 1H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.

Several neurotrophic factors are known to induce neuroprotection in traumatic injuries to the central nervous system (CNS). However, many neurotrophins are unable to attenuate cell death following CNS injuries. New data generated in our laboratory show that a suitable combination of neurotrophic factors may enhance the neuroprotective efficacy of neurotrophins on cell and tissue injury and improve sensory motor functions. This novel aspect of neurotrophins treatment in combination in spinal cord injury (SCI) induced behavioral dysfunctions and spinal cord pathology is examined in a rat model. Our investigations suggest that a suitable combination of neurotrophins will attenuate both neural and non-neural (glial cells and endothelial cells) damage in SCI leading to enhanced neuroprotection. The possible cellular and molecular mechanisms of synergistic effects of some neurotrophins in combination are still speculative and require further investigation.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.

Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

The biological basis of male–female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals 1 , 2 , but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids 3 to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids—namely androgens—lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans. Experiments in cerebral organoids show that sex hormones have a role in regulating the number of excitatory neurons in the human neocortex, providing insight into the mechanistic basis of sex-related brain differences in humans.

Background and Objectives Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. Methods In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH) SMI35 , tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing–remitting and secondary progressive MS). Results NfH SMI35 levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle ( p  = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 ( p  = 0.03) and at day 8 ( p  ≤ 0.001). S-100B protein levels decreased significantly ( p  ≤ 0.05) during treatment with TCA. Conclusion NfH SMI35 levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfH SMI35 and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.

Parvalbumin-expressing interneurons regulate the activation and fate choice of adult neural stem cells. Cell fate in the adult mammalian brain The mammalian brain is capable of generating new nerve cells into adulthood and has a number of specialized stem-cell niches for the purpose. Previous studies have examined the mechanisms that regulate the late stages of adult neurogenesis, but little is known about how quiescent neural stem cells are regulated. Here, Juan Song and colleagues use genetic and optogenetic methods to demonstrate a role for parvalbumin-expressing (PV1) interneurons, but not other inhibitory neuron subtypes, in driving fate decisions for radial glia-like quiescent neural stem cells in the adult mouse hippocampus. The study identifies a niche cell–signal–receptor trio and local circuits that provide a mechanism through which quiescent adult neural stem cells can undergo activation and self-renewal in response to neuronal activity and experience. Adult neurogenesis arises from neural stem cells within specialized niches 1 , 2 , 3 . Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival 1 , 3 . It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells 4 , 5 , 6 , 7 , 8 , 9 (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ 2 -subunit-containing GABA A receptors. Clonal analysis 9 of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ 2 . RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV + ) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV + interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV + interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division 8 . Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.

Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.