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

Abstract

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD. K E Y W O R D Saging, brain vasculature, cerebral blood flow, cognitive decline, functional MRI, mTOR

Hypertension-induced cognitive impairment: from pathophysiology to public health

“…The National Institutes of Health and other organizations have made it a priority to fund research into microvascular contributions to the pathogenesis of VCI and AD, including the role of hypertension-induced microvascular damage. New therapeutic strategies aimed at reversing ageing-induced and hypertension-induced cardiovascular and cerebromicrovascular impairment include use of mitochondrial antioxidants 153 , 179 , polyphenols and other activators of NRF2 and sirtuin 1 (refs 150 , 180 ), senolytics 181 – 184 , anti-inflammatory interventions 185 , agents that rescue cellular energetics 128 , 186 and/or prevent cellular NAD + depletion 135 , 152 , AMPK activators 187 and mTOR inhibitors 188 .…”

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