Dineley, K. T. | bioRxiv Science

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2017

LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

Dynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.

neuroscience↗