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

doi:10.1111/acel.13057

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

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-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 language	English
Article number	e13057
Journal	Aging Cell
Volume	19
Issue number	1
DOIs	https://doi.org/10.1111/acel.13057
State	Published - 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

Access to Document

10.1111/acel.13057

Cite this

Van Skike, C. E., Lin, A. L., Roberts Burbank, R., Halloran, J. J., Hernandez, S. F., Cuvillier, J., Soto, V. Y., Hussong, S. A., Jahrling, J. B., Javors, M. A., Hart, M. J., Fischer, K. E., Austad, S. N., & Galvan, V. (2020). mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Aging Cell, 19(1), [e13057]. https://doi.org/10.1111/acel.13057

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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.",

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

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: {\textcopyright} 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

year = "2020",

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doi = "10.1111/acel.13057",

language = "English",

volume = "19",

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T1 - mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging

AU - Van Skike, Candice E.

AU - Lin, Ai Ling

AU - Roberts Burbank, Raquel

AU - Halloran, Jonathan J.

AU - Hernandez, Stephen F.

AU - Cuvillier, James

AU - Soto, Vanessa Y.

AU - Hussong, Stacy A.

AU - Jahrling, Jordan B.

AU - Javors, Martin A.

AU - Hart, Matthew J.

AU - Fischer, Kathleen E.

AU - Austad, Steven N.

AU - Galvan, Veronica

N1 - 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.

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Y1 - 2020/1/1

N2 - 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.

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KW - cerebral blood flow

KW - cognitive decline

KW - functional MRI

KW - mTOR

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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