Agastra, E. | Search bioRxiv

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↗

bioRxiv2025

Tau drives cell specific functional isolation of the hippocampal formation

A major challenge in understanding Alzheimers disease is linking changes that occur across different biological scales. For example, how do changes in individual neurons build into widespread network disruptions? To address this, we used flexible mesh electronics to record neuronal activity for six months in ThyTau22 mice, a model of tauopathy that accumulates mutant human tau with age. Electrophysiology was recorded simultaneously from the hippocampus and entorhinal cortex of awake, behaving mice. At all ages we observed neuron-level, tau-driven silencing including ages without detectable tangles or cell-death. We found an unexpected phenomenon: neurons silenced by tau spontaneously recover individual firing patterns, yet these neurons fail to regain normal network interactions. Thus, as the animals age, disrupted network-level activity emerges. Specifically, we observe a global decrease in excitatory interactions and a breakdown in gamma-band coherence, which is particularly disrupted between the entorhinal cortex and hippocampus. These observations reveal a temporal relationship between neuronal silencing and impaired network connectivity, which also contributes to a progressive disruption in the excitatory/inhibitory balance. This ultimately disconnects viable entorhinal-hippocampal connections, physiologically isolating the hippocampus. Importantly, this network dysfunction is not driven by neuron loss, but by the failure of neurons to re-establish proper network interactions after silencing. This reveals a previously unrecognized mechanism by which mutant tau can destabilize neural systems. Further, these experiments indicate that a therapeutic window may exist where neuronal function and network activity might still be restored prior to irreversible degeneration.

neuroscience↗