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Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment.
Am J Physiol Heart Circ Physiol. 2018 04 01; 314(4):H693-H703.AJ

Abstract

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.

Authors+Show Affiliations

Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas.Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas.Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas.Department of Neurosurgery, University of Texas Health San Antonio , San Antonio, Texas. Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas.Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas. Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas.Department of Geriatric Medicine and Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma.Department of Cellular and Structural Biology, South Texas Research Facility Neuroscience Center, University of Texas Health San Antonio, San Antonio, Texas.Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas. Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas.

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

29351469

Citation

Van Skike, Candice E., et al. "Inhibition of mTOR Protects the Blood-brain Barrier in Models of Alzheimer's Disease and Vascular Cognitive Impairment." American Journal of Physiology. Heart and Circulatory Physiology, vol. 314, no. 4, 2018, pp. H693-H703.
Van Skike CE, Jahrling JB, Olson AB, et al. Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol. 2018;314(4):H693-H703.
Van Skike, C. E., Jahrling, J. B., Olson, A. B., Sayre, N. L., Hussong, S. A., Ungvari, Z., Lechleiter, J. D., & Galvan, V. (2018). Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment. American Journal of Physiology. Heart and Circulatory Physiology, 314(4), H693-H703. https://doi.org/10.1152/ajpheart.00570.2017
Van Skike CE, et al. Inhibition of mTOR Protects the Blood-brain Barrier in Models of Alzheimer's Disease and Vascular Cognitive Impairment. Am J Physiol Heart Circ Physiol. 2018 04 1;314(4):H693-H703. PubMed PMID: 29351469.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment. AU - Van Skike,Candice E, AU - Jahrling,Jordan B, AU - Olson,Angela B, AU - Sayre,Naomi L, AU - Hussong,Stacy A, AU - Ungvari,Zoltan, AU - Lechleiter,James D, AU - Galvan,Veronica, Y1 - 2017/12/22/ PY - 2018/1/20/pubmed PY - 2019/1/8/medline PY - 2018/1/20/entrez KW - blood-brain barrier KW - brain endothelium KW - cerebrovasculature KW - mammalian/mechanistic target of rapamycin KW - rapamycin SP - H693 EP - H703 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 314 IS - 4 N2 - An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/29351469/Inhibition_of_mTOR_protects_the_blood_brain_barrier_in_models_of_Alzheimer's_disease_and_vascular_cognitive_impairment_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.00570.2017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -