GENETIC REDUCTION OF MTOR SIGNALING AMELIORATES ALZHEIMER'S DISEASE-RELATED COGNITIVE DEFICITS AND AMYLOID-B PATHOLOGY BY RESTORING HIPPOCAMPAL GENE EXPRESSION SIGNATURE

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Background: Vascular pathology is a major feature of Alzheimer’s disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease and reduces amyloid-beta accumulation in (h)APP transgenic mice modeling AD. Methods: To investigate the effects of reduction of mTOR activity by rapamycin on hemodynamic, vascular and metabolic functions in brains of hAPPmicewe usedmulti-metric imaging systems (MRI and PET).Results: Our results demonstrate that hAPP mice have significantly reduced cerebral blood flow (CBF) and vascular density that is not related to metabolic changes, especially in areas that have a prominent role in learning and memory. Chronic rapamycin restored vascular density and CBF, reduced vascular amyloidosis and microhemorrhages, decreased amyloid burden, and relieved AD-like cognitive deficits in hAPP mice. Reduction of mTOR activity also restored CBF in aged rats and in a model of atherosclerosis, suggesting that the mechanisms bywhich attenuation of mTOR activity restores CBF are common to different models of vascular disease, and to brain aging. In vivo multiphoton imaging of brain vessels revealed that rapamycin induced an increase in nitric oxide (NO) in vascular endothelium that was followed by vasodilation. Administration of an inhibitor of NO synthases reversed the protective effects of rapamycin on brain blood flow and vascular density, indicating that rapamycin preserves vascular integrity and CBF in AD mouse brains through NO signaling. Conclusions: Our data suggest that the preservation of vascular density and brain blood flow may be key to the maintenance of cognitive function in the hAPP mouse model of AD. Rapamycin, an FDA-approved drug that is already used in the clinic, may have promise as a therapy for AD and possibly for age-associated brain diseases beyond AD alone.