mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging

Candice E. Van Skike, Ai Ling Lin, Raquel Roberts Burbank, Jonathan J. Halloran, Stephen F. Hernandez, James Cuvillier, Vanessa Y. Soto, Stacy A. Hussong, Jordan B. Jahrling, Martin A. Javors, Matthew J. Hart, Kathleen E. Fischer, Steven N. Austad, Veronica Galvan

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.

Original languageEnglish
Article numbere13057
JournalAging Cell
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2020

Bibliographical note

Funding Information:
We would like to acknowledge the technical expertise of Greg Friesenhahn for performing the blood rapamycin measurements using HPLC-tandem MS. The authors would also like to acknowledge the following funding support: Alzheimer's Association AARF-17-504221 (CEV), Ellison Medical Foundation AG-NS-0726-10 (VG), US Department of Veterans Affairs Biomedical Laboratory Research and Development Service (VA-BLRDS) Merit Award I01 BX002211-01A2 (VG), NIH/NIA R01AG057964-01 (VG), the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer's Fund in memory of Jo Nell Bailey (VG), William & Ella Owens Medical Research Foundation Grant (VG, SNA), the San Antonio Medical Foundation (VG), the JMR Barker Foundation (VG), NCATS/NIH UL1 TR002645 (VG), VA-BLRDS 1 IK2 BX003798-01A1 (SAH), NIH Biology of Aging Training Grant T32 AG-021890 (CEV, SAH, JBJ), NIH/NIA K01AG040164 (ALL), NIH/NIA R01AG054459 (ALL), NIH/NIA R01AG062480 (ALL), American Federation for Aging Research Grant #A12474 (ALL), NIH/CTSA UL1TR0000117 (ALL), NIH/NIA RC2 AG036613, and P30 AG13319-15S1 (SNA, KEF). The studies used the services of the San Antonio Nathan Shock Center of Excellence in the Biology of Aging (NIH/NIA 2 P30 AG013319-21). The authors declare no competing financial interests.

Funding Information:
We would like to acknowledge the technical expertise of Greg Friesenhahn for performing the blood rapamycin measurements using HPLC‐tandem MS. The authors would also like to acknowledge the following funding support: Alzheimer's Association AARF‐17‐504221 (CEV), Ellison Medical Foundation AG‐NS‐0726‐10 (VG), US Department of Veterans Affairs Biomedical Laboratory Research and Development Service (VA‐BLRDS) Merit Award I01 BX002211‐01A2 (VG), NIH/NIA R01AG057964‐01 (VG), the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer's Fund in memory of Jo Nell Bailey (VG), William & Ella Owens Medical Research Foundation Grant (VG, SNA), the San Antonio Medical Foundation (VG), the JMR Barker Foundation (VG), NCATS/NIH UL1 TR002645 (VG), VA‐BLRDS 1 IK2 BX003798‐01A1 (SAH), NIH Biology of Aging Training Grant T32 AG‐021890 (CEV, SAH, JBJ), NIH/NIA K01AG040164 (ALL), NIH/NIA R01AG054459 (ALL), NIH/NIA R01AG062480 (ALL), American Federation for Aging Research Grant #A12474 (ALL), NIH/CTSA UL1TR0000117 (ALL), NIH/NIA RC2 AG036613, and P30 AG13319‐15S1 (SNA, KEF). The studies used the services of the San Antonio Nathan Shock Center of Excellence in the Biology of Aging (NIH/NIA 2 P30 AG013319‐21). The authors declare no competing financial interests.

Publisher Copyright:
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Keywords

  • aging
  • brain vasculature
  • cerebral blood flow
  • cognitive decline
  • functional MRI
  • mTOR

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint

Dive into the research topics of 'mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging'. Together they form a unique fingerprint.

Cite this