mTOR drives cerebral blood flow and memory deficits in LDLR^−/− mice modeling atherosclerosis and vascular cognitive impairment

Abstract

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging

“…In aged rats, chronic mTOR inhibition with rapamycin, an intervention that extends lifespan (Wilkinson et al, ), ameliorated mTOR‐dependent decline in learning and memory in aging at least partly through the restoration of cerebrovascular function and synaptic structure. Together with our previous studies, these data indicate that mTOR drives cerebrovascular dysfunction both in normative aging and in age‐associated disease states, including AD and cognitive impairment associated with vascular disease (Halloran et al, ; Jahrling et al, ; Lin et al, , ; Van Skike et al, ) and thereby suggests that brain microvascular dysfunction may link aging to an increased risk of AD. Therefore, mTOR attenuation provides a strategy to preserve synaptic and cerebrovascular function during aging and may help to reduce the risk of AD.…”

“…We have previously shown that mTOR inhibition attenuates cognitive dysfunction in aged mice (Halloran et al, ). We and others have also shown that chronic mTOR attenuation with rapamycin can prevent and reverse cognitive and cerebrovascular deficits in several independent mouse models of AD (Lin et al, , ;Van Skike et al, ) and vascular cognitive impairment (Jahrling et al, ), leading to improved cerebrovascular function and preserved cognitive outcomes in these models of age‐related disease. The contribution of mTOR to cerebrovascular deficits is associated with normative aging, though its impact on cognitive outcomes remains unknown.…”

“…Decreased brain perfusion during normative aging has been established (Melamed, Lavy, Bentin, Cooper, & Rinot, ), and we recently showed that mTOR mediates cerebrovascular dysfunction in two different mouse models of AD (Lin et al, , ) and in a model of cognitive impairment associated with atherosclerosis (Jahrling et al, ). To define the role of cerebrovascular dysfunction in impaired sensory‐evoked functional hyperemia in aged rats (Figure ), we used arterial spin labeling MRI to measure global and regional resting CBF in adult and aged rat groups (Figure ).…”

“…For instance, near complete inhibition of mTOR activation during LTP with pharmacogenetics (Stoica et al, ) and hyperactivation of mTOR arising from functional loss of negative regulators of the kinase (Lugo et al, ) are both detrimental to neuronal function. In contrast, studies have demonstrated that moderate reduction of mTOR activity by ~25%–30% consistently improves aspects of brain function in models of aging (Halloran et al, ) and of age‐associated neurological disease (Jahrling et al, ; Lin et al, , ; Van Skike et al, ). Additionally, the mild effects of mTOR inhibition on neuronal function may be a consequence of the relatively poor blood–brain barrier permeability of these compounds (~12,500 fold lower in brain relative to blood, as reported in the methods section).…”

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

“…Mice were feeding in Shaoxing City People's Hospital experimental animal centre. Following adaptation to their environment for 1 week, the LDLR−/− mice were randomized into four dietary groups as follows: mice fed with a standard diet (NC group), mice fed a high‐fat diet (20% fat, 20% sugar and 1.25% cholesterol) (HF group), mice fed a high‐fat diet with FA supplementation (75 ug/kg/d20) (HF + FA group) and mice fed a high‐fat diet with rapamycin (10 mg/kg21) (HF + RAPA group). Folic acid was once‐daily oral gavage for 16 weeks; the control and high‐fat groups received saline by oral gavage.…”