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 Apr 1;314(4):H693-H703. doi: 10.1152/ajpheart.00570.2017. Epub 2017 Dec 22.

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.

Keywords: blood-brain barrier; brain endothelium; cerebrovasculature; mammalian/mechanistic target of rapamycin; rapamycin.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Animals
  • Behavior, Animal*
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / enzymology
  • Blood-Brain Barrier / pathology
  • Cell Line
  • Cognition*
  • Dementia, Vascular / drug therapy*
  • Dementia, Vascular / enzymology
  • Dementia, Vascular / pathology
  • Dementia, Vascular / psychology
  • Disease Models, Animal
  • Female
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Kinase Inhibitors / pharmacology*
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tight Junction Proteins / metabolism
  • Tight Junctions / drug effects
  • Tight Junctions / enzymology
  • Tight Junctions / pathology

Substances

  • Protein Kinase Inhibitors
  • Receptors, LDL
  • Tight Junction Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • Sirolimus