mTOR in cerebrovascular disease

Recent research suggests cerebrovascular dysfunction is an early pathological event in Alzheimer’s disease (AD) progression [1]. Our lab and others have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) mediates several different aspects of cerebrovascular dysfunction in AD models, including bloodbrain barrier (BBB) breakdown, cerebral hypoperfusion, reduced cerebrovascular reactivity, and impaired neurovascular coupling (please see [2] for a review of these mechanisms). However, recent data suggests mTOR activity may contribute to cerebrovascular dysfunction arising from primary vascular impairment [3], and therefore the mTOR pathway may be a critical effector of cerebrovascular dysfunction in disorders of both neurological and non-neurological etiology. We have recently reported cognitive impairments in high-fat diet fed LDL receptor null (HFD-LDLR) mice, a model of atherosclerosis [3]. We propose that this model recapitulates critical aspects of vascular cognitive impairment (VCI) because cognitive impairment in this model has a purely vascular etiology. In addition, we have shown that VCI in HFD-LDLR mice is dependent on mTOR-driven cerebrovascular dysfunction, including cerebral hypoperfusion evidenced by reduced cerebral blood flow [3], and BBB breakdown [4]. Attenuation of mTOR via rapamycin restores cerebrovascular dysfunction in HFD-LDLR mice [3, 4], and is associated with improved cognitive outcomes [3]. Additionally, mTOR inhibition has been shown to reduce atherosclerotic lesions in the aortic arch of HFDLDLR mice, even though hypercholesterolemia was not reduced [3], indicating that some of the improvements in cerebrovascular function may have originated from effects mediated through enhanced cardiovascular factors. Therefore, it is likely that restoration of cerebral blood flow by mTOR attenuation is due to the combined amelioration of both cerebrovascular (loss of brain vascular density, BBB breakdown) and cardiovascular pathologies in the HFDLDLR model of VCI. These data therefore suggest that the mTOR pathway drives both cardiovascular and cerebrovascular dysfunction in a model of cognitive impairment where the primary injury is cardiovascular pathophysiology. While these studies do not rule out that cerebrovascular Editorial