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

• Published in: Journal of cerebral blood flow and metabolism Vol. 37; no. 1; pp. 217 - 226
• Main Authors: Lin, Ai-Ling, Jahrling, Jordan B, Zhang, Wei, DeRosa, Nicholas, Bakshi, Vikas, Romero, Peter, Galvan, Veronica, Richardson, Arlan
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2017
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - pathology; Animals; Apolipoprotein E4 - genetics; Blood-Brain Barrier - drug effects; Cerebrovascular Circulation - drug effects; Glucose Metabolism Disorders - drug therapy; Learning Disabilities - drug therapy; Learning Disabilities - prevention & control; Metabolic Diseases - drug therapy; Mice; Mice, Transgenic; Neuroimaging; Original; Secondary Prevention - methods; Secondary Prevention - trends; Sirolimus - pharmacology; Sirolimus - therapeutic use; Vascular Diseases - drug therapy; Brain imaging; blood–brain barrier; cognition; Alzheimer’s disease; cerebral glucose metabolism; inflammation; APOE4; cerebral blood flow; rapamycin
• DOI: 10.1177/0271678X15621575
• ISSN: 0271-678X

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.