Subtle genomic DNA damage induces intraneuronal production of amyloid-ß (1-42) by increasing ß-secretase activity.

Aberrant accumulation of amyloid-ß (Aß) in brain is the major trigger for pathogenesis in Alzheimer's disease (AD). It is imperative to understand how Aß attains such toxic levels in the brain parenchyma. We detected that a subtle and tolerable amount of DNA damage, related to aging, increased intraneuronal Aß1-42 production both in cultured neuron and in cortex of rodent brain. Strikingly, we also observed elevated levels of mitochondrial fusion and of its major driver protein, MFN2. Hyperfusion of mitochondria may be seen as an adaptive stress response resulting from the induction of ER stress since we detected the activation of both PERK and IRE1α arms of unfolded protein response of ER stress. We found increased phosphorylation of PERK substrate eukaryotic initiation factor 2 α (eIF2α), and upregulation of the downstream effector proteins, ATF4 and CHOP. Concomitantly, increased XBP1 level, the direct effecter protein of IRE-1α, was observed. Reports suggest that eIF2α phosphorylation can increase BACE1 activity, the rate limiting enzyme in Aß production. Here, we show that inhibiting PERK, decreased Aß1-42 level while direct BACE1 inhibition, reduced the mitochondrial fusion. We found increased MFN2 expression in young 5xFAD mice when Aß plaques and neurodegeneration were absent. Thus, our study indicates that mild DNA damage leads to increased Aß1-42 production almost as a consequence of an initial ER stress-directed protective mitochondrial fusion in brain. We propose that an age-related subtle genomic DNA damage may trigger enhanced intraneuronal Aß1-42 production in an apparently healthy neuron way before the appearance of clinical symptoms in AD.

TIMP-1: A key cytokine released from activated astrocytes protects neurons and ameliorates cognitive behaviours in a rodent model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by two pathologic species, extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles. Astrocytes that maintain normal homeostasis in the brain undergo a set of molecular, cellular and functional changes called reactive astrogliosis in various neurological diseases including AD. It is hypothesized that reactive astrocytes initially tend to protect neurons by reducing Aß load and by secreting a plethora of cytokines, however, their functions have only been poorly investigated. Our studies on the kinetics of activation of cortical astrocytes following Aß-exposure revealed significant level of activation as early as in 6 h. The astrocyte conditioned medium (ACM) from 6 h Aß-treated astrocytes (Aß-ACM) provided significant neuroprotection of cultured cortical neurons against Aß insults. Analysis of the secreted proteins in Aß-ACM revealed a marked increase of Tissue inhibitor of Metalloproteinase-1 (TIMP-1) within 6 h. Interestingly, we found that neutralization of TIMP-1 with antibody or knockdown with siRNA in astrocytes abolished most of the neuroprotective ability of the 6 h Aß-ACM on Aß-treated cultured neurons. Furthermore addition of exogenous rat recombinant TIMP-1 protein protects primary neurons from Aß mediated toxicity. In a well characterized Aß-infused rodent model of AD, intra-cerebroventricular administration of TIMP-1 revealed a reduction in Aß load and apoptosis in hippocampal and cortical regions. Finally, we found that TIMP-1 can ameliorate Aß-induced cognitive dysfunctions through restoration of Akt and its downstream pathway and maintenance of synaptic integrity. Thus, our results not only provide a functional clarity for TIMP-1, secreted by activated astrocytes, but also support it as a major candidate in cytokine-mediated therapy of AD especially at the early phase of disease progression.

COVID-19: Are we dealing with a multisystem vasculopathy in disguise of a viral infection?

After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic with unprecedented global response. With the expanding domain of presentations in COVID-19 patients, the full range of manifestations is yet to unfold. The classical clinical symptoms for SARS-CoV-2 affected patients are dry cough, high fever, dyspnoea, lethal pneumonia whereas many patients have also been found to be associated with a few additional signs and clinical manifestations of isolated vasculopathy. Albeit a deep and profound knowledge has been gained on the clinical features and management of COVID-19, less clear association has been provided on SARS-CoV-2 mediated direct or indirect vasculopathy and its possible correlation with disease prognosis. The accumulative evidences suggest that novel coronavirus, apart from its primary respiratory confinement, may also invade vascular endothelial cells of several systems including cerebral, cardio-pulmonary as well as renal microvasculature, modulating multiple visceral perfusion indices. Here we analyse the phylogenetic perspective of SARS-CoV-2 along with other strains of ß-coronaviridae from a standpoint of vasculopathic derangements. Based on the existing case reports, literature and open data bases, we also analyse the differential pattern of vasculopathy related changes in COVID-19 positive patients. Besides, we debate the need of modulation in clinical approach from a hemodynamical point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV-2 affected patients.

Medha Plus - A novel polyherbal formulation ameliorates cognitive behaviors and disease pathology in models of Alzheimer's disease.

Alzheimer's disease (AD) is a multi-faceted neurodegenerative disorder that leads to drastic cognitive impairments culminating in death. Pathologically, it is characterized by amyloid-ß (Aß) plaques, neurofibrillary tangles and neurodegeneration in brain. Complete cure of AD remains elusive to date. Available synthetic drugs only provide symptomatic reliefs targeting single molecule, hence, are unable to address the multi-factorial aspects in AD pathogenesis. It is imperative to develop combinatorial drugs that address the multiple molecular targets in AD. We show a unique polyherbal formulation of Brahmi, Mandukaparni, Shankhpushpi, Yastimadhu, Kokilaksha and Shunthi called 'Medha Plus' (MP), conventionally used for improving memory and reducing anxiety, was able to ameliorate cognitive deficits and associated pathological hallmarks of AD. Viability assays revealed that MP prevented Aß-induced loss of neurites as well as neuronal apoptosis in cellular models. An array of behavioral studies showed that MP was able to recover AD-associated memory deficits in both Aß-injected rats and 5XFAD mice. Immunohistochemical studies further revealed that MP treatment reduced Aß depositshpi and decreased apoptotic cell death in the hippocampus. Enzymatic assays demonstrated anti-oxidative and anti-acetyl cholinesterase properties of MP especially in hippocampus of Aß-injected rats. An underlying improvement in synaptic plasticity was observed with MP treatment in 5XFAD mice along with an increased expression of phospho-Akt at serine 473 indicating a role of PI3K/Akt signaling in correcting these synaptic deficits. Thus, our strong experiment-driven approach shows that MP is an incredible combinatorial drug that targets multiple molecular targets with exemplary neuroprotective properties and is proposed for clinical trial.

Astrocyte subtype-specific approach to Alzheimer's disease treatment.

Astrocytes respond to any pathological condition in the central nervous system (CNS) including Alzheimer's disease (AD), and this response is called astrocyte reactivity. Astrocyte reaction to a CNS insult is a highly heterogeneous phenomenon in which the astrocytes undergo a set of morphological, molecular and functional changes with a characteristic secretome profile. Such astrocytes are termed as 'reactive astrocytes'. Controversies regarding the reactive astrocytes abound. Recently, a continuum of reactive astrocyte profiles with distinct transcriptional states has been identified. Among them, disease-associated astrocytes (DAA) were uniquely present in AD mice and expressed a signature set of genes implicated in complement cascade, endocytosis and aging. Earlier, two stimulus-specific reactive astrocyte subtypes with their unique transcriptomic signatures were identified using mouse models of neuroinflammation and ischemia and termed as A1 astrocytes (detrimental) and A2 astrocytes (beneficial) respectively. Interestingly, although most of the A1 signature genes were also detected in DAA, as opposed to A2 astrocyte signatures, some of the A1 specific genes were expressed in other astrocyte subtypes, indicating that these nomenclature-based signatures are not very specific. In this review, we elaborate the disparate functions and cytokine profiles of reactive astrocyte subtypes in AD and tried to distinguish them by designating neurotoxic astrocytes as A1-like and neuroprotective ones as A2-like without directly referring to the A1/A2 original nomenclature. We have also focused on the dual nature from a functional perspective of some cytokines depending on AD-stage, highlighting a number of them as major candidates in AD therapy. Therefore, we suggest that promoting subtype-specific beneficial roles, inhibiting subtype-specific detrimental roles or targeting subtype-specific cytokines constitute a novel therapeutic approach to AD treatment.

Modulation of α-Synuclein Fibrillation by Ultrasmall and Biocompatible Gold Nanoclusters.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, the pathogenesis of which is closely linked to the misfolding and aggregation of the neuronal protein α-Synuclein (A-Syn). Numerous molecules that inhibit/modulate the pathogenic aggregation of A-Syn in an effort to tackle PD pathogenesis have been reported, but none so far have been successful in treating the disease at the clinic. One major reason for this is the poor blood-brain barrier (BBB) permeability of most of the molecules being used. Therefore, using BBB-permeable (and biocompatible) nanomaterials as fibrillation modulators is gaining importance. In the present work, we show how nontoxic and ultrasmall gold nanoclusters (AuNCs) can systematically modulate the pathogenic fibrillation of A-Syn in vitro, based on the chemical nature of their capping agents, using two reported easily synthesizable AuNCs as models. In addition, we detect the BBB permeability in mice of one of these AuNCs solely by making use of its intrinsic fluorescence. Thus, our work exemplifies how AuNCs can be potential therapeutics against PD; while also acting as fluorescent probes for their own BBB permeability.

Neuroinvasive potential of a primary respiratory pathogen SARS- CoV2: Summarizing the evidences.

BACKROUND AND AIMS: After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in SARS-CoV-2 pandemic with unfathomable global responses. The characteristic clinical symptoms for Coronavirus (COVID-19) affected patients are high fever, dry-cough, dyspnoea, lethal pneumonia whereas some patients also show additional neurological signs such as headache, nausea, vomiting etc. The accumulative evidences suggest that SARS-CoV-2 is not only confined within the respiratory tract but may also invade the central nervous system (CNS) and peripheral nervous system (PNS) inducing some fatal neurological diseases. Here, we analyze the phylogenetic perspective of SARS-CoV-2 with other strains of ß-Coronaviridae from a standpoint of neurological spectrum disorders. METHODOLOGY: A Pubmed/Medline, NIH Lit Covid, Cochrane library and some open data bases (BioRxiv, MedRxiv,preprint.org and others) search were carried out by using keywords relevant to our topic of discussion. The extracted literatures are scrutinized by the authors. RESULTS: 58 literatures including original articles, case reports and case series were selected by the authors to analyze the differential distribution of neurological impairments in COVID-19 positive patients along with angiotensin-converting enzyme-2 (ACE2) expression dynamics in neuronal and non-neuronal tissue in CNS and PNS with neuroinvasive potential of SARS-CoV2. CONCLUSION: We discuss the need for modulations in clinical approach from a neurological point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV2 positive patients.

An aminoglycoside antibiotic inhibits both lipid-induced and solution-phase fibrillation of α-synuclein in vitro.

Parkinson's disease (PD), closely associated with the misfolding and aggregation of the neuronal protein α-synuclein (A-Syn), is a neurodegenerative disorder with no cure to date. Here, we show that the commercially available, inexpensive, aminoglycoside antibiotic kanamycin effectively inhibits both lipid-induced and solution-phase aggregation of A-Syn in vitro, pointing towards the prospective repurposing of kanamycin as a potential anti-PD drug.