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mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.
J Cereb Blood Flow Metab. 2018 01; 38(1):58-74.JC

Abstract

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR-/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Authors+Show Affiliations

1 Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX, USA.2 Sanders-Brown Center on Aging, Department of Pharmacology and Nutritional Sciences and Department of Biomedical Engineering, University of Kentucky, KY, USA.1 Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX, USA.1 Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX, USA.1 Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX, USA.3 Department of Pharmacology, University of Texas Health Science Center at San Antonio, TX, USA.4 Department of Psychiatry, University of Texas Health Science Center at San Antonio, TX, USA.5 Department of Medicine, University of Texas Health Science Center at San Antonio, TX, USA.6 Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, TX, USA.6 Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, TX, USA. 7 Department of Biochemistry, University of Texas Health Science Center at San Antonio, TX, USA.1 Department of Cellular and Integrative Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, TX, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

28511572

Citation

Jahrling, Jordan B., et al. "MTOR Drives Cerebral Blood Flow and Memory Deficits in LDLR-/- Mice Modeling Atherosclerosis and Vascular Cognitive Impairment." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 38, no. 1, 2018, pp. 58-74.
Jahrling JB, Lin AL, DeRosa N, et al. MTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment. J Cereb Blood Flow Metab. 2018;38(1):58-74.
Jahrling, J. B., Lin, A. L., DeRosa, N., Hussong, S. A., Van Skike, C. E., Girotti, M., Javors, M., Zhao, Q., Maslin, L. A., Asmis, R., & Galvan, V. (2018). MTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 38(1), 58-74. https://doi.org/10.1177/0271678X17705973
Jahrling JB, et al. MTOR Drives Cerebral Blood Flow and Memory Deficits in LDLR-/- Mice Modeling Atherosclerosis and Vascular Cognitive Impairment. J Cereb Blood Flow Metab. 2018;38(1):58-74. PubMed PMID: 28511572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment. AU - Jahrling,Jordan B, AU - Lin,Ai-Ling, AU - DeRosa,Nicholas, AU - Hussong,Stacy A, AU - Van Skike,Candice E, AU - Girotti,Milena, AU - Javors,Martin, AU - Zhao,Qingwei, AU - Maslin,Leigh Ann, AU - Asmis,Reto, AU - Galvan,Veronica, Y1 - 2017/05/17/ PY - 2017/5/18/pubmed PY - 2018/12/26/medline PY - 2017/5/18/entrez KW - Atherosclerosis KW - cerebral blood flow KW - cognition KW - inflammation KW - vascular biology SP - 58 EP - 74 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J. Cereb. Blood Flow Metab. VL - 38 IS - 1 N2 - We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR-/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/28511572/mTOR_drives_cerebral_blood_flow_and_memory_deficits_in_LDLR_/__mice_modeling_atherosclerosis_and_vascular_cognitive_impairment_ L2 - http://journals.sagepub.com/doi/full/10.1177/0271678X17705973?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -