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J Cereb Blood Flow Metab. 2017 Jan;37(1):217-226. Epub 2015 Dec 31.

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.

Author information

1
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA ailing.lin@uky.edu.
2
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
3
Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA.
4
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
5
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
6
Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
7
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
8
Geriatric Medicine, University of Oklahoma Health Science Center and Oklahoma City VA Medical Center, Oklahoma City, OK, USA.

Abstract

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.

KEYWORDS:

APOE4; Alzheimer’s disease; Brain imaging; blood–brain barrier; cerebral blood flow; cerebral glucose metabolism; cognition; inflammation; rapamycin

PMID:
26721390
PMCID:
PMC5167110
DOI:
10.1177/0271678X15621575
[Indexed for MEDLINE]
Free PMC Article

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