Biology subjects

Gundavelli, A.

Publications and source records attributed to Gundavelli, A..

2 recordsLinked to original sources

bioRxiv2026

Subcellular Spatial Profiling Unveils Links Between Neuritic Plaques with Selective Tau Vulnerability in Alzheimer's Disease

Alzheimer's disease (AD) features widespread extracellular amyloid-{beta} plaques but selective intraneuronal tau accumulation in cortical layers II/III and V, while layer IV remains relatively resistant. Here, we combined subcellular spatial transcriptomics with co-registered A{beta} and pTau immunohistochemistry to determine why neurons exposed to comparable plaque-associated pathology differ in somatic pTau accumulation. Plaque-associated neuritic stress occurred similarly across layers, but layer IV neurons showed attenuated pTau accumulation and reduced somatic expression of a shared neurite-soma stress program involving DCTN1, CALM3, NORAD, and PIN1. Trajectory analysis within layers identified tau-vulnerable and resistant neuronal states implicating calcium signaling, retrograde transport, and lysosomal function. Notably, astrocytic APOE-neuronal LRP1 co-expression increased significantly along the pTau-vulnerable trajectory, and APOE {epsilon}4 was associated with stronger coupling of local plaque pathology to pTau-associated molecular programs. These findings reveal neuronal programs and neuron-glia interactions underlying selective tau vulnerability and resistance in AD, highlighting potential tau-targeting therapeutics.

neuroscience↗

bioRxiv2026

Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies

Cerebrovascular alterations are widely observed in both Alzheimers Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Picks disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.

neuroscience↗