期刊
JOURNAL OF NEUROSCIENCE
卷 41, 期 19, 页码 4305-4320出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2144-20.2021
关键词
Alzheimer's disease; cerebral blood flow; cerebrovascular dysfunction; mTOR; neurovascular coupling; nNOS
资金
- National Institutes of Health (NIH) \ National Institute on Aging (NIA) [1R01-AG-057964-01, 1R01-AG-068283-01]
- U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service Merit Review Award [I01 BX002211-01A2]
- San Antonio Nathan Shock Center of Excellence in the Biology of Aging [NIA 2-P30-AG-013319-21]
- San Antonio Medical Foundation
- J.M.R. Barker Foundation
- Alzheimer's Association [AARF-17-504221]
- U.S. Department of Veteran's Affairs BiomedicalLaboratory Research and Development Grant [CDA-2 IK2 BX003798-01A1]
- NIH Kirschstein Predoctoral Individual National Research Service Award [1F31-AG067732-01]
- NIH South Texas Medical Scientist Training Program [T32-GM-113896]
- San Antonio Nathan Shock Center of Excellence in the Biology of Aging (NIH/NIA) [2P30AG01331921]
The study reveals that in an Alzheimer's disease model, mTOR drives impairments in neurovascular coupling (NVC) through inhibition of neuronal nitric oxide synthase (nNOS) and non-NOS-dependent components. However, attenuation of mTOR activity effectively restores NVC function and can even enhance it above normal responses. This suggests that targeting mTOR may be a potential treatment for Alzheimer's disease and other neurological diseases associated with aging.
Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling (NVC), a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS (nNOS)-and non-NOS-dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Restoration of NVC and concomitant reduction of cortical amyloid-beta levels effectively treated memory deficits in 12-month-old hAPP(J20) mice. These data indicate that mTOR is a critical driver of NVC dysfunction and underlies cognitive impairment in an AD model. Together with our previous findings, the present studies suggest that mTOR promotes cerebrovascular dysfunction in AD, which is associated with early disruption of nNOS activation, through its broad negative impact on nNOS as well as on non-NOS components of NVC. Our studies highlight the potential of mTOR attenuation as an efficacious treatment for AD and potentially other neurologic diseases of aging.
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