Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease

Ai Ling Lin, Wei Zheng, Jonathan J. Halloran, Raquel R. Burbank, Stacy A. Hussong, Matthew J. Hart, Martin Javors, Yen Yu Ian Shih, Eric Muir, Rene Solano Fonseca, Randy Strong, Arlan G. Richardson, James D. Lechleiter, Peter T. Fox, Veronica Galvan

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.

Original languageEnglish (US)
Pages (from-to)1412-1421
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • Alzheimer?s disease
  • age-associated
  • cerebral amyloid angiopathy
  • nitric oxide synthase
  • rapamycin
  • target-of-rapamycin (TOR)
  • vascular dysfunction

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease'. Together they form a unique fingerprint.

Cite this