mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimers disease with cerebral amyloid angiopathy

Authors

Van Skike, C. E., Hernandez, S. F., Hussong, S. A., Miller, L. R., Makhlouf, H., Muppala, A., DeRosa, N., Jahrling, J. B., Dineley, K. T., Galvan, V.

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid {beta} fibrils (A{beta}) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimers disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular A{beta} lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular A{beta} fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar A{beta} load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar A{beta}, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Jun 2026.

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