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

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.

Caloric restriction preserves memory and reduces anxiety of aging mice with early enhancement of neurovascular functions

“…The preservation of hippocampal and frontal CBF were associated with improved cognition in the old CR mice. This is also consistent with our previous findings that restoration of CBF in young mice modeling human AD could potentially prevent their cognitive decline in aging [30, 35]. …”

“…In addition to modulating eNOS, we previously demonstrated that mTOR inhibition reduces proinflammatory cytokine that breaks down BBB, and thus restores BBB integrity and CBF in mice that carries human APOE4 gene [35]. Furthermore, mTOR is able to clean up misfolded proteins (such as Aβ and cerebral amyloid angiopathy) via regulation of autophagy [36], therefore, it can further reduce athero-sclerosis and preserve neurovascular integrity, e.g., vascular density [30].…”

mTOR: Alzheimer's disease prevention for APOE4 carriers

“…Therefore, early interventions that can restore neurovascular deficits to normal could be critical in potentially preventing the development of AD-related neuropathology and cognitive impairment. In a recent study, using magnetic resonance imaging (MRI), Lin et al reported that young, asymptomatic APOE4 targeted-replacement mice treated with rapamycin had restored CBF and BBB integrity to the level of wild-type controls [2]. The preserved vasculature was associated with amelioration of incipient learning deficits of the APOE4 transgenic mice.…”

“…Lin et al demonstrated that mTOR inhibition reduced proinflammatory pathways in brain vasculature that otherwise impair BBB integrity in the APOE4 transgenic mice [2]. Loss of BBB integrity is considered one of the initiating events that lead to AD-like pathological cascade in the APOE4 carriers [1].…”

“…Loss of BBB integrity is considered one of the initiating events that lead to AD-like pathological cascade in the APOE4 carriers [1]. Restoring BBB integrity is highly associated with improved CBF and preserved learning ability of the APOE4 transgenic mice [2]. In addition, Lin et al previously reported that inhibition of mTOR activates endothelial nitric oxide synthase and causes the release of nitric oxide, a vasodilator, which in turn increases CBF [7].…”