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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 β-Coronaviridae from a standpoint of neurological spectrum disorders. 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. 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. 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. • Comparative phylogenetic analysis reveals the neuroinvasive potential of SARS-CoV2. • ACE2 expression in neuronal and neuro-glial cells augment neurotropism of SARS-CoV2. • Clinical manifestations of COVID-19 from the neurological perspective were presented. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in Aβ-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Aβ treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro. Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic gene BCL2-like 11 (Bim). Conversely, FoxO1 responded to Aβ insult by binding to the Trib3 gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy.Wefound that Trib3 indirectly activates unc-51-like autophagy-activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from Aβ insult. Our results suggest that a self-amplifying feed-forward loop among Trib3, Akt, and FoxO1 in Aβ-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Bim is a pro-apoptotic member of the Bcl-2 family that is induced and contributes to neuron death in response to nerve growth factor (NGF) deprivation. Past work has revealed that Bim is downstream of multiple independent transcriptional pathways in neurons, including those culminating in activation of the c-Jun, FoxO, and Myb transcription factors. This study addresses the issue of whether the three signaling pathways are redundant with respect to Bim induction or whether they act cooperatively. Examination of the proximal Bim promoter reveals binding sites for FoxO, Mybs, and, as shown here, c-Jun. We find that mutation of any one of these types of sites abolishes induction of a Bim promoter-driven reporter in response to NGF deprivation. Moreover, down-regulation of either c-Jun, FoxOs, or Mybs by short hairpin RNAs blocks induction of Bim promoter-reporter activity triggered by withdrawal of NGF, This was the case for reporters driven by either the proximal promoter or a promoter that also includes additional regulatory elements in the first intron of the Bim gene. Such short hairpin RNAs also suppressed the induction of endogenous Bim protein. These findings thus indicate that the Bim promoter acts as a coincidence detector that optimally responds to the simultaneous activation of three different pro-apoptotic transcriptional pathways. Such a mechanism provides a ‘fail-safe’ that prevents neurons from dying by accidental activation of any single pathway. It also permits neurons to utilize individual pathways such as JNK signaling for other purposes without risk of demise. [ABSTRACT FROM AUTHOR]

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. • A continuum of reactive astrocyte states exist in Alzheimer's disease (AD). • Astrocyte reactivity is a complex response with neuroprotective and neurotoxic aspects. • Reactive astrocyte subtypes – A1-like and A2-like – have distinct cytokine profiles. • Astrocyte subtype-specific cytokine-based therapies emerge as a prudent approach. [ABSTRACT FROM AUTHOR]

Long-term potentiation (LTP) and long-term depression (LTD) are considered to be the cellular mechanisms behind the increase or decrease of synaptic strength respectively. Electrophysiologically induced LTP/LTD is associated with the activation of glutamate receptors in the synaptic terminals resulting in the initiation of biochemical processes in the postsynaptic terminals and thus propagation of synaptic activity. Isolated nerve endings i.e. synaptosome preparation was used to study here, the biochemical phenotypes of LTP and LTD, and glutamate treatment in varying concentration for different time was used to induce those biochemical phenomena. Treatment with 200 μM glutamate showed increased GluA1 phosphorylation at serine 831 and activation of CaMKIIα by phosphorylation at threonine 286 like LTP, whereas 100 μM glutamate treatment showed decrease in GluA1 phosphorylation level at both pGluA1(S831) and pGluA1(S845), and activation of GSK3β by de-phosphorylating pGSK3β at serine 9 like LTD. The 200 μM glutamate treatment was associated with an increase in the local translation of Arc, BDNF, CaMKIIα and Homer1, whereas 100 μM glutamate treatments resulted in decrease in the level of the said synaptic proteins and the effect was blocked by the proteasomal inhibitor, Lactasystin. Both, the local translation and local degradation was sensitive to the Ca2+ chellator, Bapta-AM, indicating that both the phenomena were dependent on the rise in intra-synaptosomal Ca2+, like LTP and LTD. Overall the results of the present study suggest that synaptosomal preparations can be a viable alternative to study mechanisms underlying the biochemical activities of LTP/LTD in short term. • 200 μM Glutamate treatment induces local translation in synaptosomes. • Exposure to 100 μM and 200 μM Glutamate shows LTD and LTP like activity respectively in the synaptosomes. • 100 μM Glutamate treatment induces local degradation of proteins in the synaptosomes. • Both, local translation and local degradation are dependent on Ca2+ increase. • Local translation is dependent on BDNF-TrkB signaling, but local degradation is not. [ABSTRACT FROM AUTHOR]

Background: β-Amyloid-induced neuron death and degeneration is considered to be central to the pathogenesis of Alzheimer disease. Results: p53-up-regulated modulator of apoptosis (Puma), a protein of the B-cell lymphoma-2 family, is induced by transcription factor FoxO3a and participates in neuron death in response to β-amyloid. Conclusion: β-Amyloid-induced neuron death requires induction of Puma. Significance: Puma could be a potential target for disease therapeutics. Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of the Bcl-2 family play an essential role in various cell death paradigms, including neurodegeneration. Here we report that Puma (p53-up-regulated modulator of apoptosis), an important member of the BH3-only protein family, is up-regulated in neurons upon toxic β-amyloid 1-42 (Aβ(1-42)) exposure both in vitro and in vivo. Down-regulation of Puma by specific siRNA provides significant protection against neuron death induced byAβ(1-42).Wefurther demonstrate that the activation of p53 and inhibition of PI3K/Akt pathways induce Puma. The transcription factor FoxO3a, which is activated when PI3K/Akt signaling is inhibited, directly binds with thePumagene and induces its expression upon exposure of neurons to oligomeric Aβ(1-42). Moreover, Puma cooperates with another BH3-only protein, Bim, which is already implicated in AD. Our results thus suggest that Puma is activated by both p53 and PI3K/Akt/FoxO3a pathways and cooperates with Bim to induce neuron death in response to Aβ(1-42). [ABSTRACT FROM AUTHOR]

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-β (Aβ) 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 Aβ-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 Aβ-injected rats and 5XFAD mice. Immunohistochemical studies further revealed that MP treatment reduced Aβ 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 Aβ-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. [Display omitted] • Polyherbal formulation Medha Plus (MP) attenuates Aβ accumulation in Aβ-infused rodents. • AChE activity and mitochondrial ROS generation was attenuated by MP. • MP restores the pre- and post-synaptic markers in 5xFAD mice. • MP enhances the phosphorylation of Akt in AD models. • MP protects neurons from Aβ induced toxicity leading to restoration of memory in AD rodents. [ABSTRACT FROM AUTHOR]

Abstract: We review here evidence defining a molecular pathway that includes cell cycle-related molecules and that appears to play a required role in neuron death during normal development as well as in disease and trauma. The pathway starts with inappropriate activation of cyclin dependent kinase 4 (Cdk4) in neurons which leads to hyper-phosphorylation of the pRb family member p130. This in turn results in dissociation of p130 and its associated chromatin modifiers Suv39H1 and HDAC1 from the transcription factor E2F4. Dissociation of this complex results in de-repression of genes with E2F binding sites including those encoding the transcription factors B- and C-Myb. Once elevated in neurons, B- and C-Myb proteins bind to the promoter for the pro-apoptotic BH3-only protein Bim and promote its induction. Bim then interacts with the core cellular apoptotic machinery, leading to caspase activation and apoptotic death. This pathway is supported by a variety of observations and experimental findings that implicate it as a required element for neuron loss in development and in many nervous system traumas and disorders. The components of this pathway appear to represent potential therapeutic targets for prevention of disease-associated neuron death. [Copyright &y& Elsevier]

Smokeless tobacco (SLT) or chewing tobacco is very common addiction practice in India across the ages making a somber threat and huge disease burden. Oral use of SLT is often assorted with many ingredients and is capable to induce extreme toxicological challenges and carcinogenic developments. The current study investigated the systemic stress in human subjects using blood parameters of SLT chewers. Perturbations in parameters of metabolism, inflammation, RBC morphology and enhanced apoptosis of PBMC in SLT-chewers compared to non-chewer human subjects were found. The study further delved whether SLT mediated any neurodegeration. In vitro studies using SLT showed the neuronal cell death in a dose dependent manner compromising the mitochondrial health. Apoptosis was induced with the consequence of generation of reactive species, induction of DNA damage, alteration of membrane potential, mitochondrial morphology, activation of caspase-cascade, apoptotic proteins and disruption of the neuronal cytoskeleton network. To correlate the neurobiological insult of SLT, mouse behavioral studies with open-field test and plus maze and molecular analyses were investigated. This unique mechanistic study with molecular mechanism validated fatal effects of SLT and SLT-mediated neuronal cell death. [ABSTRACT FROM AUTHOR]