Hussong, S. | bioRxiv Science

bioRxiv2026

mTOR disrupts cerebrovascular RNA regulatory networks in Alzheimers disease

Cerebrovascular dysfunction is increasingly recognized as a central contributor to the initiation and progression of Alzheimer's disease (AD). The mammalian/mechanistic target of rapamycin (mTOR) pathway has emerged as a key driver of AD-related vascular dysfunction. Consistent with this role, attenuation of mTOR signaling restores multiple aspects of cerebrovascular function in AD models, including vascular density, cerebral blood flow, vascular reactivity, and neurovascular coupling. However, the molecular mechanisms linking mTOR dysregulation to cerebrovascular dysfunction in AD remain poorly understood we assessed cerebrovascular levels of RNA-regulatory proteins in hAPP(J20) mice treated with rapamycin from 6 to 12 months of age. Rapamycin partially restored disease-suppressed heterogeneous nuclear ribonucleoprotein (hnRNP) family members, including hnRNP D1 (AUF1) and hnRNP E1 (PCBP1). Rapamycin-mediated restoration of hnRNP extended to the cerebrovasculature of PS19 (P301S) tauopathy mice, indicating that mTOR-dependent hnRNP suppression is shared across amyloid- and tau-driven models of AD. Consistent with these findings, hnRNP E1 and hnRNP L each showed a nominally significant inverse relationship with Braak stage in AD patient brains, with a similar but non-significant trend for hnRNP R and hnRNP M; The coordinated pattern of decline suggests network-level disruption of RNA-binding protein homeostasis in AD. Together, our studies uncover a previously unrecognized link between mTOR signaling and the regulation of RNA-regulatory proteins and identify a previously unrecognized, reversible mTOR-dependent RNA regulatory program in the cerebrovasculature that may contribute to neurovascular dysfunction in AD and reveal new targets for therapeutic intervention.

neuroscience↗

bioRxiv2026

Soluble pathogenic tau transmission to astrocytes drives acute oxidative damage, cellular senescence, and neurovascular uncoupling in a model of Alzheimers tauopathy

We previously found that soluble pathogenic tau aggregates (tau oligomers) enter brain microvascular endothelial cells and induce cellular senescence and microvascular dysfunction in a tauopathy mouse model. This study shows that soluble pathogenic tau is also transmitted to astrocytes, where it induces mitochondrial dysfunction, mediates senescence, and impairs neurovascular coupling responses. Single-cell RNA sequencing of hTau mouse cortex revealed astrocytes as one of the most transcriptionally altered cell type, showing coordinated downregulation of electron transport chain genes and upregulation of stress-induced and inflammatory markers, also elevated in hTau mouse brain and astrocyte-enriched fractions. Similar to neuron-to-neuron transmission, soluble tau aggregates entered primary human astrocytes via a heparin-sensitive process, causing microtubule destabilization, ATP depletion, and mitochondrial ROS accumulation before induction of cell-cycle-arrest-associated markers. Mitochondrial ROS scavenging with Mito TEMPO reduced tau-induced SASP cytokine activation in astrocytes in vitro and in vivo. Coculturing neurons with astrocytes undergoing tau induced senescence decreased dendritic spine density, branch level, and dendritic area in a non-cell-autonomous manner. Tau and the SASP-associated cytokines IL-1{beta} and IL-6 contributed to distinct aspects of the neuronal structural phenotype. Astrocyte-targeted SOD2 overexpression attenuated the hTau-related deficit in evoked cerebral blood flow responses; however, this partial improvement in response magnitude and duration did not achieve statistical significance compared to hTau mice expressing GFP. These results identify astrocyte senescence as a potential mechanism connecting astrocyte tau uptake, mitochondrial stress, and neuronal structural impairment. The findings motivate further study of mitochondrial antioxidant defense in tau-associated astrocyte dysfunction.

neuroscience↗