Vascular disturbances arise earlier than brain atrophy and amyloid deposition in Alzheimer's disease. Cerebral amyloid angiopathy (deposition of amyloid-β in the walls of cerebral vessels) occurs in 90% of patients and sharply increases the risk of dementia and intracerebral hemorrhage. This work stands somewhat apart: it sits alongside research on the Alzheimer's brain, but the vascular component and the role of mTOR in it remain poorly studied. Previous work showed that mTOR mediates vascular dysfunction in other models, but the mechanism in cerebral amyloid angiopathy remained unclear.
The researchers used Tg2576 mice (an Alzheimer's disease model with extensive vascular amyloid deposits). Starting at 4 months of age, the animals received rapamycin (an mTOR inhibitor) or a placebo in their food. At 18 months, in vivo two-photon microscopy was used to measure vascular and parenchymal amyloid, vascular reactivity to acetylcholine, and blood-brain barrier permeability by dextran leakage. Microbleeds were counted on brain sections, and expression of tight junction proteins was assessed by immunofluorescence. Neurovascular coupling was measured by laser Doppler flowmetry during whisker stimulation, and the contributions of nNOS and eNOS were separated by sequential application of inhibitors. Contextual memory was tested with a fear conditioning paradigm.
Rapamycin reduced the total area of vascular fibrillar amyloid-β deposits by 40.6% and the density of vessel-associated deposits by 28.9%, without affecting parenchymal plaques or vessel density. Vascular reactivity to acetylcholine was severely impaired in amyloid-bearing segments of control Tg2576 mice, but rapamycin restored it almost to the level of segments without amyloid. Blood-brain barrier permeability (leakage of 70 kDa dextran) was significantly higher in Tg2576 mice than in wild-type mice, and rapamycin normalized it. The number of microbleeds was elevated in Tg2576 mice, and rapamycin reduced it to control levels. Expression of claudin-5 and ZO-1 increased, while MMP-9 decreased in amyloid-bearing vessels under rapamycin treatment. Neurovascular coupling was impaired in Tg2576 mice (a reduced cerebral blood flow response to whisker stimulation), but rapamycin restored it. The contextual memory deficit in Tg2576 mice was also eliminated by rapamycin.
This work is the first to show that mTOR specifically governs vascular amyloid accumulation and vascular dysfunction in a model of cerebral amyloid angiopathy, without touching parenchymal plaques. Unlike neighboring studies that focus on general neurodegeneration or parenchymal amyloid, this one highlights the vascular component and shows that it can be selectively corrected. This changes the picture of therapeutic targets: vascular pathology may be a target in its own right for mTOR inhibitors.
The field could move toward clinical trials of mTOR inhibitors in patients with cerebral amyloid angiopathy. It will be important to determine how early treatment must begin and how long it should continue. Long-term effects of mTOR suppression on other organs and systems also remain to be studied, given the known side effects of rapamycin.
The results will influence the development of therapies for Alzheimer's disease and cerebral amyloid angiopathy, as well as our understanding of the vascular component's role in neurodegeneration.
Conduct preclinical trials of rapamycin in other models of cerebral amyloid angiopathy and assess the safety of long-term use. Then move to pilot clinical studies in patients with early signs of vascular pathology.
The work links vascular dysfunction, amyloid accumulation, and cognitive impairment into a single mechanism governed by mTOR. This helps address a long-standing problem: why vascular changes precede neurodegeneration, and whether they can be reversed.
Rapamycin was discovered in a soil sample from Easter Island and was initially used as an antifungal agent, later becoming known as a geroprotector that extends the lifespan of mice.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.