Biology subjects

Barve, A.

Publications and source records attributed to Barve, A..

5 recordsLinked to original sources

bioRxiv2025

Senolytics Restore Hematopoietic Stem Cells Function in Sickle Cell Disease

Sickle Cell Disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, possibly due to pathological stress on bone marrow. To investigate this further, we interrogated mice and individuals with SCD and observed extended cell cycle times, oxidative stress, DNA damage, senescence, and dysregulation of molecular programs associated with these processes in bone marrow hematopoietic stem and progenitor cells (HSPCs). Human SCD HSPCs displayed poor hematopoietic potential ex vivo. SCD mice displayed a dramatic loss of transplantable bone marrow HSPCs, which was reversed upon treatment of SCD mice with the senolytic agent, ABT-263 (navitoclax). Thus, senolytics restore bone marrow function during SCD in mice and represent a novel strategy to improve bone marrow health in individuals with SCD and improve the safety of potentially curative gene therapies that utilize autologous HSPCs from individuals with SCD.

cell biology↗

bioRxiv2025

Reduced levels of synaptic vesicle protein 2A in the extracellular vesicles and brain of Alzheimer's disease- associations with Aβ, tau and synaptophysin

BackgroundSynaptic dysfunction plays an important role in Alzheimers disease (AD) and is an emerging imaging and fluid biomarker. Here, we aimed to assess the regional expression of synaptic vesicle glycoprotein 2A (SV2A) in the brain and extracellular vesicles of AD patients and its associations with the APOE {varepsilon}4 allele, amyloid-{beta}, tau pathologies, and other synaptic markers. MethodsMass spectrometry-based synaptosome proteomics was performed on brain-derived extracellular vesicles (BdEVs) isolated from the frontal cortex of 17 AD patients and 4 NCs. Immunohistochemical staining for SV2A, synaptophysin, amyloid-{beta} and phospho-tau was performed on postmortem tissue from the frontal, temporal, and entorhinal cortices and hippocampus of 40 AD patients and 44 nondemented controls (NCs). ResultsReduced levels of synaptic proteins, including synaptotagamin, GAP43, SYT1, SNAP25 and 14-3-3{zeta}, were positively correlated with SV2A and negatively correlated with GFAP and NEFL in BdEVs from AD patients and NCs. We detected lower levels of SV2A in the hippocampus and entorhinal cortex of AD compard to NCs, and in APOE {varepsilon}4 carriers than in noncarriers. SV2A levels were positively correlated with synaptophysin and negatively correlated with the levels of the amyloid-{beta}, phospho-tau, and Braak stages. ConclusionsThis study provides postmortem evidence of synaptic markers and reduced regional levels of SV2A in brain tissue slices and BdEVs from AD patients compared with NCs and in APOE {varepsilon}4 carriers compared to non-carriers. SV2A could serve as a valuable marker for monitoring synaptic degeneration in AD.

neuroscience↗

bioRxiv2025

Astrocyte and mitochondrial footprints in brain-derived extracellular vesicles predict tau pathology

Tauopathies are neurodegenerative disorders characterized by abnormal tau aggregation, with primary 3R (e.g., Picks disease, PiD) and 4R (e.g., progressive supranuclear palsy, PSP) variants posing a significant diagnostic challenge. Here, we examined brain-derived extracellular vesicles (BD-EVs) isolated from the prefrontal cortex of PiD (3R), PSP (4R), and non-demented controls (CTRL) to determine if these vesicles reflect disease-specific proteomic signatures. We found that while tau pathology does not substantially alter BD-EV concentration or the enrichment of core vesicular markers, it does influence their size distribution and protein cargo. BD-EV samples from PiD patients exhibited a greater abundance of small vesicles and distinct protein profiles when compared to PSP and CTRL. Weighted Gene Co-expression Network Analysis (WGCNA) identified four key protein modules to account for variance between patient groups Endoplasmic Reticulum, Mitochondria, Microtubules, and Trivalent Inorganic Cation Transport. In PiD, astrocyte-derived mitochondrial proteins were significantly elevated, whereas neuronal microtubule-related proteins were diminished relative to both PSP and CTRL. Notably, changes in the mitochondrion and microtubule modules enhanced the detection of PiD pathology. Cellular origin annotation revealed a marked shift in BD-EV composition: PiD samples exhibited an increased astrocytic signature, while both PiD and PSP showed a reduction in neuronal proteins compared to CTRL. Crucially, the enrichment of astrocytic mitochondrial and endoplasmic reticulum proteins, alongside reduced neuronal proteins, correlated strongly with the severity of tau pathology (AT8-stained aggregates) in patient brains. These findings demonstrate that BD-EVs capture tau isoform-specific cellular and molecular alterations, offering a window into disease mechanisms at the neuron-glia interface. By linking distinct protein signatures and their cellular origins to tau pathology severity, our results highlight the potential of BD-EV profiling as a biomarker strategy for distinguishing between and monitoring the progression of 3R and 4R tauopathies.

neuroscience↗

bioRxiv2024

Inverse and Postponed Impacts of Extracellular Tau PHF on Astrocytes and Neurons' Mitochondrial Function

BackgroundTauopathies encompass a spectrum of neurodegenerative disorders which are marked by the pathological aggregation of tau protein into paired helical filaments (PHF-tau), neurofibrillary tangles (NFTs) and Glial-fibrillary tangles (GFTs). These aggregates impair cellular, mitochondrial, and synaptic functions. The emergence of extracellular tau (ePHF-tau), featuring a myriad of isoforms and phosphorylation states, presents a challenge in comprehending its nuanced effects on neural cells, particularly concerning synaptic and mitochondrial integrity. MethodsWe studied the impact of ePHF-tau (2N4R) on different states and ages of primary cultures of rat neuroglia. Using confocal microscopy and proteomic analysis of synaptosomes, we studied the impact of ePHF-tau on neurite and synapse number. We monitored mitochondrial responses in neurons and astrocytes over 72 hours using advanced fluorescence microscopy for dynamic, high-throughput analysis. ResultsTreatment with ePHF-tau has a strong effect on the neurites of immature neurons, but its toxicity is negligible when the neurons are more mature. At the mature stage of their development, we observed a substantial increase in the density of the PSD-95/vGlut1 zone in neurite, suggesting altered synaptic connectivity and ePHF-tau excitotoxicity. Proteomics revealed significant changes in mitochondrial protein in synaptosomes following exposure to ePHF-tau. In the neuronal compartment, real-time imaging revealed rapid and persistent mitochondrial dysfunction, increased ATP production, and reduced mitochondrial turnover. In contrast, we observed increased mitochondrial turnover and filamentation after treatment in the astrocyte processes, indicating cell-specific adaptive responses to ePHF-tau. ConclusionsThis study sheds light on the intricate effects of extracellular tau aggregates on neuronal and astrocytic mitochondrial populations, highlighting how tau pathology can lead to mitochondrial disturbances and synaptic alterations. By delineating the differential responses of neurons and astrocytes to ePHF-tau, our findings pave the way for developing targeted therapeutic interventions to mitigate the detrimental impacts of tau aggregates in neurodegenerative diseases.

neuroscience↗

bioRxiv2018

Cell type purification by single-cell transcriptome-trained sorting

Traditional cell type enrichment using fluorescence activated cell sorting (FACS) relies on methods that specifically label the cell type of interest. Here we propose GateID, a computational method that combines single-cell transcriptomics for unbiased cell type identification with FACS index sorting to purify cell types of choice. We validate GateID by purifying various cell types from the zebrafish kidney marrow and the human pancreas without resorting to specific antibodies or transgenes.

bioinformatics↗