Biology subjects

Biswas, S. C.

Publications and source records attributed to Biswas, S. C..

8 recordsLinked to original sources

bioRxiv2026

Exosomal miR-23a release coincides with astrocytic calcineurin activation, protects neurons from apoptosis by regulating NOXA in Parkinson's disease models and is enriched in the plasma of patients with Parkinson's disease

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and degeneration of their projections in the striatum (STR) of the brain. Astrocytes are recognized as active contributors to PD pathogenesis, yet the role of calcineurin (CN), a Ca/calmodulin-dependent phosphatase which is well characterized in neurons, remains unexplored in astrocytes in the context of PD. Here, we show that CN protein expression is upregulated in the STR of MPTP-treated mice, coinciding with DA neurodegeneration and astrogliosis. In human astrocytoma cells and primary rat astrocytes, the neurotoxin Rotenone induced rapid intracellular Calcium elevation and CN activation. Unexpectedly, this was accompanied by a decrease in intracellular levels of miR-23a, an astrocyte-enriched microRNA previously linked to CN signalling in cardiomyocytes. We found that this decrease reflected active exosomal export: Rotenone increased both exosomal miR-23a levels and total exosome number, while blocking exosome biogenesis with GW4869 restored intracellular miR-23a levels. Functionally, both astrocyte-derived exosomes and miR-23a overexpression protected neuronal cells (SH-SY5Y, PC12) against Rotenone-, 6-OHDA-, and MPP+-induced toxicity. Mechanistically, miR-23a showed direct binding to the 3'UTR of the pro-apoptotic BH3-only protein NOXA, thereby suppressing its expression, subsequently attenuating caspase-3 activation. Finally, exosomal miR-23a levels were significantly elevated in plasma from PD patients compared with age-matched controls, supporting clinical relevance. Together, these findings identify a previously unrecognized astrocyte-to-neuron communication axis during PD pathogenesis, in which astrocytic CN activation accompanied by exosomal miR-23a release represents a neuroprotective stress-responsive pathway with potential biomarker and therapeutic relevance in PD.

neuroscience↗

bioRxiv2025

A unique serum-free murine cortical astrocyte culture to study endoplasmic reticulum stress in response to amyloid-β

Astrocytes are integral to understand Alzheimers disease (AD) pathology but the existing serum-supplemented in vitro astrocyte culture models are not suitable to study certain stress response mechanisms. Here, we developed a serum-free murine primary cortical astrocyte culture model to study endoplasmic reticulum (ER) stress and inflammation to see the effect of amyloid-beta (A{beta}1-42). Astrocytes were cultured in a controlled serum-free environment to minimize interference from serum components. Serum-free astrocytes were exposed to oligomeric A{beta} to induce ER stress and inflammation. Initially no significant activation of eIF2, a key marker of ER stress, was observed under serum-free condition but with the removal of N-acetyl cysteine ER stress response was enhanced after 24 hours of A{beta} exposure. Subsequently, the inflammatory response, assessed through TNF- expression, was minimal in the presence of growth factors but became pronounced when these factors were withdrawn. Astrocytic reactivity, assessed by GFAP expression, was observed with prolonged A{beta} exposure, indicating a reactive astrogliosis response. Transcript analysis revealed a time-dependent shift in the expression of inflammatory modulators, with early time points showing increased anti-inflammatory markers and late exposure promoting pro-inflammatory responses. These findings highlight the potential of serum-free cultures for studying ER stress and inflammation together in astrocytes and offer insights into the complex role of these cells in AD pathophysiology.

neuroscience↗

bioRxiv2024

Sertad1 is elevated and plays a necessary role in synaptic loss, neuron death and cognitive impairment in a model of Alzheimer's disease

Dysfunctional autophagy is a primary characteristic of Alzheimers disease (AD) pathogenesis. How autophagic impairment leads to cellular changes that contributes to AD pathogenesis remains unclear. To study this further, we assessed levels of autophagy related proteins in 5xFAD mice brain at different ages and found their robust upregulation in cortex and hippocampus suggesting increased induction of autophagy with disease progression but failed clearance. We have identified a transcriptional coregulator Sertad1, as a key mediator of dysfunctional autophagy in AD mice. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared to wild-type (WT) mice. Sertad1 knockdown in 5xFAD mice brain lowered levels of autophagy related proteins and lysosome marker, LAMP1 suggesting its role in autophagy flux modulation. FoxO3a is an important transcriptional regulator of the autophagy network and lies at the nexus of autophagy-apoptosis cross-talk. We found that Sertad1 knockdown blocked nuclear translocation of FoxO3a along with a restoration in Akt activity. Further, we showed that knockdown of Sertad1 in 5xFAD mice brain improved cognitive functions along with a remarkable restoration in synaptic health and dendritic spine density. Taken together, our results demonstrated that autophagy is robustly induced with disease progression but it is impaired; Sertad1 knockdown restored autophagy defects, synaptic loss and improved learning and memory in AD models. Thus, we propose that Sertad1 acts in a multimodal manner regulating crucial cell death pathways including apoptosis and autophagy and could be an excellent target for therapeutic intervention to combat a multifactorial disorder such as AD.

neuroscience↗

bioRxiv2024

Intercellular adhesion molecule-1 reprograms microglia to improve cognitive functions by inhibiting ERK/STAT3 signalling pathway in a model of Alzheimer's disease

BackgroundMicrogliosis is one of the early hallmarks of Alzheimers disease (AD) that plays a crucial role in AD-associated neuroinflammation. However, strategies to harness microglial activation without affecting its homeostatic function are currently lacking. Our recent finding revealed astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairment in 5xFAD mice model of AD. Here, we investigated the possible mechanism of ICAM-1 that involves modification of microglial activation state and function. MethodsWe treated primary microglia cultures with amyloid-{beta} (A{beta}) in presence or absence of ICAM-1 and then assessed microglial inflammatory activation and phagocytic clearance of A{beta} by western blotting and confocal imaging. We further treated 5xFAD mice with ICAM-1 intraperitoneally and ICAM-1 antagonist lifitegrast intranasally to assess the beneficial effect of ICAM-1 on A{beta} mediated microgliosis, synaptic protein expressions and cognitive deficits. ResultsHere we report that, ICAM-1 inhibits microglial inflammatory activation by inhibiting ERK-STAT3 pathway which is indispensable for microglial inflammation. Moreover, ICAM-1 was found to potentiate microglia to engulf and eliminate A{beta} in primary culture and reduced A{beta} plaque load and associated microglial activation in 5xFAD mice hippocampus. This reduced plaque levels and associated microgliosis in turn refurbished synaptic protein expressions and improved cognition and memory in these mice. Interestingly, ICAM-1 mediated microglial modification along with cognitive improvement was partially lost when ICAM-1-LFA-1 interaction was inhibited. ConclusionTaken together these findings delineate the importance of ERK/STAT3 pathway in A{beta} mediated microglial inflammation and the modulatory role of ICAM-1 in microglial activation and phagocytosis in order to improve clearance of A{beta} and associated memory and cognitive impairments.

neuroscience↗

bioRxiv2024

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

Parkinsons 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.

neuroscience↗

bioRxiv2023

Astroglia-derived TIMP-1 alleviates cognitive deficits by restoring synaptic plasticity in Alzheimer's disease

The influence of astrocyte-secreted cytokines on neuronal health in Alzheimers disease (AD) is poorly understood, despite their increasing recognition as potential molecules for therapeutic targeting. Recently, we demonstrated that an anti-inflammatory cytokine, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is robustly secreted by astrocytes early in response to amyloid-{beta} (A{beta}) but is reduced in its prolonged presence. Here, we found strikingly diminished levels of TIMP-1 in the brain of six-month-old 5xFAD mice concomitant with high levels of A{beta}, versus wild-type mice. Intracerebroventricular injection of TIMP-1 in 5xFAD mice ameliorated their cognitive functions. TIMP-1 not only ensured neuronal viability against apoptosis and aberrant autophagy in the AD model by binding to neuronal CD63 receptors, but also conferred synapse-specific effects. Synaptosomal analysis revealed TIMP-1 elevates dendritic spine size and protein levels, likely by promoting post-synaptic long-term potentiation in hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. Therefore, we identify TIMP-1 as a multifunctional cytokine with distinct protective mechanisms-of-action on neurons and propose it as a promising therapeutic candidate in AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/533245v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@187adadorg.highwire.dtl.DTLVardef@9b6ae1org.highwire.dtl.DTLVardef@185e352org.highwire.dtl.DTLVardef@10f2995_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Rheb-mTOR Activation Rescues Amyloid Beta-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 post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimers disease patients brain suggests ineffective target cytokine mRNA suppression by existing microRNPs in diseased brain. Exploring the mechanism of amyloid beta induced cytokine expression, we have identified how the inactivation of the repressive miR-146 microRNPs 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 mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling and retarded Ago2-cytokine mRNA interaction in rat astrocyte cells. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 microRNPs in amyloid beta exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimers disease.

neuroscience↗

bioRxiv2020

Fruit bromelain derived peptides destabilize growth of amyloidal fibrils

{beta}-Amyloid deposition as fibrillar plaques in brain is the primary cause of Alzheimers disease. We report potency of cysteine protease fruit bromelain from pineapple in destabilising A{beta} fibrils. Bromelain peptide pool (Mw<500 Da) obtained mimicking human alimentary tract digestion inhibited fibrillation from monomeric and oligomeric states of A and irreversibly dissociated preformed fibrils into small oligomers of varied sizes. Time kinetics was followed by Thioflavin-T assay and microscopic imaging. Synthetic bromelain peptides corresponding to A{beta} sticky region found using ClustalW analysis revealed specificity of peptides in destabilisation of amyloidal structures. Spectra of different molecular states of A{beta} obtained from application of 8-anilino-1-naphthalenesulfonic acid, circular dichroism and Fourier-Transformed Infrared spectroscopy collectively indicated interaction dependent structural change. Probable mechanism for fibril dissociation was thus predicted. Peptides relieved A{beta} cytotoxicity on pheochromcytoma cells and dissociated plaques in AD-type rats prepared by bilateral intracerebroventricular administration of A{beta} in rat brain cortex. Pineapple being a phytoceutical, its efficiency to disaggregate amyloid bodies warrant further investigation. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗