MTOR attenuation with rapamycin reverses neurovascular uncoupling and memory deficits in mice modeling alzheimer's Disease

Candice E. Van Skike, Stacy A. Hussong, Stephen F. Hernandez, Andy Q. Banh, Nicholas DeRosa, Veronica Galvan

Research output: Contribution to journalArticlepeer-review

Abstract

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-b 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.

Original languageEnglish (US)
Pages (from-to)4305-4320
Number of pages16
JournalJournal of Neuroscience
Volume41
Issue number19
DOIs
StatePublished - May 12 2021

Keywords

  • Alzheimer's disease
  • Cerebral blood flow
  • Cerebrovascular dysfunction
  • MTOR
  • NNOS
  • Neurovascular coupling

ASJC Scopus subject areas

  • Neuroscience(all)

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