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.

ICAM-1 protects neurons against Amyloid-ß and improves cognitive behaviors in 5xFAD mice by inhibiting NF-κB.

Alzheimer's disease (AD) is mainly characterized by amyloid beta (Aß) plaque deposition and neurofibrillary tangle formation due to tau hyperphosphorylation. It has been shown that astrocytes respond to these pathologies very early and exert either beneficial or deleterious effects towards neurons. Here, we identified soluble intercellular adhesion molecule-1 (ICAM-1) which is rapidly increased in astrocyte conditioned medium derived from Aß1-42 treated cultured astrocytes (Aß1-42-ACM). Aß1-42-ACM was found to be neuroprotective, however, Aß1-42-ACM deprived of ICAM-1 was unable to protect neurons against Aß1-42 mediated toxicity. Moreover, exogenous ICAM-1 renders protection to neurons from Aß1-42 induced death. It blocks Aß1-42-mediated PARP cleavage and increases the levels of anti-apoptotic proteins such as Bcl-2 and Bcl-xL, and decreases pro-apoptotic protein Bim. In an Aß-infused rat model of AD and in 5xFAD mouse, intra-peritoneal administration of ICAM-1 revealed a reduction in Aß load in hippocampal and cortical regions. Moreover, ICAM-1 treatment led to an increment in the expression of the Aß-degrading enzyme, neprilysin in 5xFAD mice. Finally, we found that ICAM-1 can ameliorate cognitive deficits in Aß-infused rat and 5xFAD mouse. Interestingly, ICAM-1 could block the NF-κB upregulation by Aß and inhibition of NF-κB recovers cognitive impairments in 5xFAD mice. Thus, our study finds a neuroprotective role of ICAM-1 and suggests that it can be a major candidate in cytokine-mediated therapy of AD.

Forkhead Box O3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of p53 up-regulated modulator of apoptosis (Puma) in a model of Parkinson's disease.

Parkinson's disease (PD) results from the selective loss of dopaminergic neurons of substantia nigra pars compacta region of the midbrain. It has been reported that the transcription factor forkhead Box O3a (FoxO3a) is activated and induces pro-apoptotic protein such as Bcl-2-interacting mediator of cell death (BIM) and p53 up-regulated modulator of apoptosis (PUMA) in variety of neuron death paradigms. Activity of FoxO3a is governed by its post-translational modifications which control its subcellular localization. Aim of this study was to determine whether FoxO3a is activated and up-regulates its pro-apoptotic genes to induce neuron death in PD. We exposed neuronal PC12 cells or primary cultures of dopaminergic neurons to 6-hydroxy dopamine (6-OHDA) and infused 6-OHDA in rat brain to develop PD models. We found that FoxO3a undergoes multiple post-translational modifications which render its nuclear localization in dopaminergic neuronal cells in response to 6-OHDA. The nuclear redistribution of FoxO3a is significantly increased in dopaminergic neurons of 6-OHDA infused rat brains as well. Moreover, FoxO3a is required for dopaminergic neurodegeneration in response to 6-OHDA as RNAi-mediated silencing of FoxO3a protects these cells from 6-OHDA toxicity. In a search of the downstream targets we identified PUMA as a direct target of FoxO3a. By knocking down FoxO3a we could successfully block the up-regulation of the pro-apoptotic protein PUMA in this model. Recently, it has been reported that chromatin remodeler SWItch/sucrose non-fermentable binds to FOXO and activates transcription. We found that Brg-associated factor 57 (BAF57), a subclass of SWItch/sucrose non-fermentable is up-regulated and play a necessary role in neuron death induced by 6-OHDA. Moreover, it is required for induction of PUMA by FoxO3a in this cellular model of PD. Taken together, our study suggest that FoxO3a is activated, translocates to nucleus, induces its pro-apoptotic target PUMA in the presence of chromatin remodeler BAF57 to execute neuron death in cellular models of PD.

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.

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease.

Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.

Small-Molecule Cdc25A Inhibitors Protect Neuronal Cells from Death Evoked by NGF Deprivation and 6-Hydroxydopamine.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that are presently incurable. There have been reports of aberrant activation of cell cycle pathways in neurodegenerative diseases. Previously, we have found that Cdc25A is activated in models of neurodegenerative diseases, including AD and PD. In the present study, we have synthesized a small library of molecules targeting Cdc25A and tested their neuroprotective potential in cellular models of neurodegeneration. The Buchwald reaction and amide coupling were crucial steps in synthesizing the Cdc25A-targeting molecules. Several of these small-molecule inhibitors significantly prevented neuronal cell death induced by nerve growth factor (NGF) deprivation as well as 6-hydroxydopamine (6-OHDA) treatment. Lack of NGF signaling leads to neuron death during development and has been associated with AD pathogenesis. The NGF receptor TrkA has been reported to be downregulated at the early stages of AD, and its reduction is linked to cognitive failure. 6-OHDA, a PD mimic, is a highly oxidizable dopamine analogue that can be taken up by the dopamine transporters in catecholaminergic neurons and can induce cell death by reactive oxygen species (ROS) generation. Some of our newly synthesized molecules inhibit Cdc25A phosphatase activity, block loss of mitochondrial activity, and inhibit caspase-3 activation caused by NGF deprivation and 6-OHDA. Hence, it may be proposed that Cdc25A inhibition could be a therapeutic possibility for neurodegenerative diseases and these Cdc25A inhibitors could be effective treatments for AD and PD.

Single point mutations at the S129 residue of α-synuclein and their effect on structure, aggregation, and neurotoxicity.

Parkinson's disease is an age-related neurological disorder, and the pathology of the disease is linked to different types of aggregates of α-synuclein or alpha-synuclein (aS), which is an intrinsically disordered protein. The C-terminal domain (residues 96-140) of the protein is highly fluctuating and possesses random/disordered coil conformation. Thus, the region plays a significant role in the protein's solubility and stability by an interaction with other parts of the protein. In the current investigation, we examined the structure and aggregation behavior of two artificial single point mutations at a C-terminal residue at position 129 that represent a serine residue in the wild-type human aS (wt aS). Circular Dichroism (CD) and Raman spectroscopy were performed to analyse the secondary structure of the mutated proteins and compare it to the wt aS. Thioflavin T assay and atomic force microscopy imaging helped in understanding the aggregation kinetics and type of aggregates formed. Finally, the cytotoxicity assay gave an idea about the toxicity of the aggregates formed at different stages of incubation due to mutations. Compared to wt aS, the mutants S129A and S129W imparted structural stability and showed enhanced propensity toward the α-helical secondary structure. CD analysis showed proclivity of the mutant proteins toward α-helical conformation. The enhancement of α-helical propensity lengthened the lag phase of fibril formation. The growth rate of ß-sheet-rich fibrillation was also reduced. Cytotoxicity tests on SH-SY5Y neuronal cell lines established that the S129A and S129W mutants and their aggregates were potentially less toxic than wt aS. The average survivability rate was ∼40% for cells treated with oligomers (presumably formed after 24 h of incubation of the freshly prepared monomeric protein solution) produced from wt aS and ∼80% for cells treated with oligomers obtained from mutant proteins. The relative structural stability with α-helical propensity of the mutants could be a plausible reason for their slow rate of oligomerization and fibrillation, and this was also the possible reason for reduced toxicity to neuronal cells.

Brain-enriched miR-128: Reduced in exosomes from Parkinson's patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the death of mid-brain dopaminergic neurons. Unfortunately, no effective cure or diagnostic biomarkers for PD are available yet. To address this, the present study focuses on brain-enriched small non-coding regulatory RNAs called microRNAs (miRNAs) that are released into the circulation packaged inside small extracellular vesicles called exosomes. We collected blood samples from PD patients and isolated exosomes from the plasma. qPCR-based detection revealed a particular neuron-enriched miR-128 to be significantly decreased in the patient-derived exosomes. Interestingly, a concomitant decreased expression of miR-128 was observed in the cellular models of PD. Fluorescent live cell imaging and flow-cytometry revealed that over-expression of miR-128 can prevent 6-OHDA-mediated mitochondrial superoxide production and induction of neuronal death respectively. This neuroprotective effect was found to be induced by miR-128-mediated inhibition of FoxO3a activation, a transcription factor involved in apoptosis. miR-128 over-expression also resulted in down-regulation of pro-apoptotic FoxO3a targets- FasL and PUMA, at both transcript and protein levels. Further downstream, miR-128 over-expression inhibited activation of caspases-8, -9 and -3, preventing both the intrinsic and extrinsic pathways of apoptosis. Additionally, over expression of miR-128 prevented down-regulation of synaptic proteins- Synaptophysin and PSD-95 and attenuated neurite shortening, thereby maintaining overall neuronal integrity. Thus, our study depicts the intracellular role of miR-128 in neuronal apoptosis and neurodegeneration and its implications as a biomarker being detectable in the circulating exosomes of PD patient blood. Thus, characterization of such exosomal brain-enriched miRNAs hold promise for effective detection and diagnosis of PD.

Predictors and Pathway of Maternal Near Miss: A Case-Control Study in a Tertiary Care Facility in Kolkata.

Background: Use of maternal near-miss (MNM) cases as an adjunct has been advocated to understand the processes of obstetric care because they share similar pathways as maternal deaths. Identifying the predictors and care pathway is crucial to improve the quality of care and end preventable maternal deaths. Materials and Methods: This case-control study was conducted at a tertiary care facility in Kolkata from May 2019 to March 2020. Women admitted with complications during pregnancy, childbirth, or within 42 days of postpartum, who met the World Health Organization (WHO) near-miss criteria, were identified as cases, and equivalent age-group matched controls were recruited. Sample size of 60 cases and 60 controls was estimated, assuming a power of 80%, level of significance 0.05, and case-control ratio of 1. After obtaining approval from the institutional ethics committee and informed written consent from the participants, data was collected through face-to-face interview and review of records. Statistical analysis including care pathway analysis (using three-delay model) was performed using Statistical Package for Social Sciences version 16. Results: Joint family type (adjusted odds ratio [AOR] [CI] = 5.06 [1.48, 7.28]), lack of antenatal checkups (AOR [CI] = 7.85 [1.47, 12.09]), previous history of cesarean section (AOR [CI] = 3.94 [1.09, 14.33]), first delay in seeking care (AOR [CI] = 13.84 [3.62, 32.83]), and preexisting medical disorders (AOR [CI] = 11.03 [4.62, 22.80]) were identified as significant predictors of MNM in the adjusted model. Significant difference in the proportion of first and second delays in the care pathway was observed between cases and controls. Conclusions: Identification of risk factors of MNM and pattern of delays in the care pathway will help improving quality of obstetric care.

Sertad1 plays an essential role in developmental and pathological neuron death.

Developmental and pathological death of neurons requires activation of a defined pathway of cell cycle proteins. However, it is unclear how this pathway is regulated and whether it is relevant in vivo. A screen for transcripts robustly induced in cultured neurons by DNA damage identified Sertad1, a Cdk4 (cyclin-dependent kinase 4) activator. Sertad1 is also induced in neurons by nerve growth factor (NGF) deprivation and Abeta (beta-amyloid). RNA interference-mediated downregulation of Sertad1 protects neurons in all three death models. Studies of NGF withdrawal indicate that Sertad1 is required to initiate the apoptotic cell cycle pathway since its knockdown blocks subsequent pathway events. Finally, we find that Sertad1 expression is required for developmental neuronal death in the cerebral cortex. Sertad1 thus appears to be essential for neuron death in trophic support deprivation in vitro and in vivo and in models of DNA damage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.

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.

BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-ß.

Alzheimer's disease (AD) is characterized by accumulation of senile amyloid-ß (Aß) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aß toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aß treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aß. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aß-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aß treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.

Rheb-mTOR activation rescues Aß-induced cognitive impairment and memory function by restoring miR-146 activity in glial cells.

Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at the post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer's disease patients' brain suggests ineffective target cytokine mRNA suppression by existing micro-ribonucleoproteins (miRNPs) in diseased brain. Exploring the mechanism of amyloid beta-induced cytokine expression, we have identified how the inactivation of the repressive miR-146 miRNPs causes increased production of cytokines in amyloid beta-exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer-induced sequestration of the mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling, and retarded Ago2-cytokine mRNA interaction in rat astrocytes. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 miRNPs in amyloid beta-exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimer's disease.

Glutamate treatment mimics LTP- and LTD-like biochemical activity in viable synaptosome preparation.

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 GSK3ß by de-phosphorylating pGSK3ß 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.

Small Non-coding RNAs: Do They Encode Answers for Controlling SARS-CoV-2 in the Future?

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus responsible for the current COVID-19 (coronavirus disease 2019) pandemic, which has hit the world since December 2019. It has spread to about 216 countries worldwide, affecting more than 21.7 million people so far. Although clinical trials of a number of promising antiviral drugs and vaccines against COVID-19 are underway, it is hard to predict how successful these drug- or vaccine-based therapeutics are eventually going to be in combating COVID-19 because most of such therapeutic strategies have failed against human coronaviruses such as SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus) responsible for similar pandemics in the past. In that context, we would like to bring to scientific attention another group of endogenous regulatory molecules, the small non-coding RNAs, especially the microRNAs, which are found to regulate critical cellular pathways in a number of disease conditions, including RNA viral infections. This review will focus on understanding the effect of altered microRNA expression during coronavirus-mediated infections and how it may provide clues for further exploring the pathogenesis of SARS-CoV-2, with a view of developing RNAi-based therapeutics and biomarkers against COVID-19.

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.

Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis.

The molecules that mediate neuron death in Alzheimer's disease (AD) are largely unknown. We report that beta-amyloid (Abeta), a death-promoting peptide implicated in the pathophysiology of AD, induces the proapoptotic protein Bcl-2 interacting mediator of cell death (Bim) in cultured hippocampal and cortical neurons. We further find that Bim is an essential mediator of Abeta-induced neurotoxicity. Our examination of postmortem AD human brains additionally reveals upregulation of Bim in vulnerable entorhinal cortical neurons, but not in cerebellum, a region usually unaffected by AD. Accumulating evidence links inappropriate induction/activation of cell cycle-related proteins to AD, but their roles in the disease have been unclear. We find that the cell cycle molecule cyclin-dependent kinase 4 (cdk4) and its downstream effector B-myb, are required for Abeta-dependent Bim induction and death in cultured neurons. Moreover, neurons that overexpress Bim in AD brains also show elevated levels of the cell cycle-related proteins cdk4 and phospho-Rb. Our observations indicate that Bim is a proapoptotic effector of Abeta and of dysregulated cell cycle proteins in AD and identify both Bim and cell cycle elements as potential therapeutic targets.

Cell cycle molecules define a pathway required for neuron death in development and disease.

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.

Glucagon-like peptide-1 (GLP-1) diminishes neuronal degeneration and death caused by NGF deprivation by suppressing Bim induction.

Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone most intensively studied for its actions on insulin secreting beta-cells. GLP-1 and its receptor are also found in brain and accumulating evidence indicates that GLP-1 has neuroprotective actions. Here, we investigated whether GLP-1 protects neuronal cells from death evoked by nerve growth factor (NGF) withdrawal. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer disease to diabetic neuropathies. We report that GLP-1 provides sustained protection of cultured neuronal PC12 cells and sympathetic neurons from degeneration and death caused by NGF deprivation. Past work shows that NGF deprivation induces the pro-apoptotic protein Bim which contributes to neuron death. Here, we find that GLP-1 suppresses Bim induction promoted by NGF deprivation. Thus, GLP-1 may protect neurons, at least in part, by suppressing Bim induction. Our findings support the idea that drugs that mimic or elevate GLP-1 represent potential therapeutics for neurodegenerative diseases.

RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation.

The molecules underlying neuron loss in Parkinson's disease (PD) are essentially unknown, and current therapies focus on diminishing symptoms rather than preventing neuron death. We identified RTP801 as a gene whose transcripts were highly induced in a cellular model of PD in which death of neuronal catecholaminergic PC12 cells was triggered by the PD mimetic 6-OHDA. Here, we find that RTP801 protein is also induced in this and additional cellular and animal PD models. To assess the relevance of these observations to PD, we used immunohistochemistry to compare RTP801 expression in postmortem brains from PD and control patients. For all PD brains examined, expression was highly elevated within neuromelanin-containing neurons of the substantia nigra but not in cerebellar neurons. Evaluation of the potential role of RTP801 induction in our cellular model revealed that RTP801 overexpression is sufficient to promote death but does not further elevate death caused by 6-OHDA. Furthermore, RTP801 induction is requisite for death in our cellular PD models and in 6-OHDA-treated cultured sympathetic neurons in that its knockdown by short hairpin RNAs (shRNAs) is protective. The mechanism by which 6-OHDA and RTP801 induce neuron death appears to involve repression of mammalian target of rapamycin (mTOR) kinase activity, and such death is inhibited by shRNAs targeting TSC2 (tuberous sclerosis complex), a protein with which RTP801 interacts to block mTOR activation. Our findings thus suggest that the elevation of RTP801 we detect in PD substantia nigral neurons may mediate their degeneration and death and that RTP801 and its signaling cascade may be novel potential therapeutic targets for the disease.