期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 37, 期 1, 页码 217-226出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X15621575
关键词
Brain imaging; rapamycin; APOE4; cerebral blood flow; cerebral glucose metabolism; cognition; blood-brain barrier; inflammation; Alzheimer's disease
资金
- National Institute on Aging (NIA) of NIH [K01AG040164]
- NIH CTSA at the University of Kentucky [UL1TR0000117]
- Veterans Administration Research and Development Merit Award [5I01BX002211-01A2]
- Robert L. Bailey and Daughter Lisa K. Bailey Alzheimer's Fund
- William & Ella Owens Medical Research Foundation
- JMR Barker Foundation
- NIA [2T32AG021890-11]
Apolipoprotein E epsilon 4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E epsilon 4 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 presymptomatic Apolipoprotein E epsilon 4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E epsilon 4 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 epsilon 4 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 epsilon 4 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.
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