CVN‐AD Alzheimer's mice show premature reduction in neurovascular coupling in response to spreading depression and anoxia compared to aged controls

Abstract

We compared the efficacy of neurovascular coupling and substrate supply in cerebral cortex during severe metabolic challenges in transgenic Alzheimer's [CVN‐AD] and control [C57Bl/6] mice, to evaluate the hypothesis that metabolic insufficiency is a critical component of degeneration leading to dementia. We analyzed cerebral blood flow and metabolic responses to spreading depression (induced by K+ applied to the cortex) and anoxia across aging in CVN‐AD + C57Bl/6 genotypes. In the CVN‐AD genotype progression to histological and cognitive hallmarks of dementia is a stereotyped function of age. We correlated physiology and imaging of the cortex with the blood flow responses measured with laser doppler probes. The results show that spreading depression resulted in a hyperemic blood flow response that was dramatically reduced (24% in amplitude, 70% in area) in both middle‐aged and aged CVN‐AD mice compared to C57Bl/6 age‐matched controls. However, spreading depression amplitude and conduction velocity (≈6 mm/min) did not differ among groups. Anoxia (100% N2) showed significantly decreased (by 62%) reactive blood flow and autoregulation in aged AD‐CVN mice compared to aged control animals. Significantly reduced neurovascular coupling occurred prematurely with aging in CVN‐AD mice. Abbreviated physiological hyperemia and decreased resilience to anoxia may enhance early‐onset metabolic deficiency through decreased substrate supply to the brain. Metabolic deficiency may contribute significantly to the degeneration associated with dementia as a function of aging and regions of the brain involved.

Contrasting Metabolic Insufficiency in Aging and Dementia

“…Importantly, the critical neuronal functions which nNOS subserves (ie, neurovascular coupling) are intact in the CVN-AD model. We have confirmed the preservation of these important NO-signaling cascades and neurovascular coupling in the young CVN-AD and mNOS2 -/-animals [16,28,95].…”

“…This dynamic regulation of blood flow by neuronal activity is called neurovascular coupling, where neurons, astrocytes and blood vessels interact to continuously match substrate supply (through blood flow) with ongoing metabolic requirements. In the transition between aging, mild cognitive impairment, and dementia both neurovascular coupling and blood brain barrier function are progressively perturbed [16]. These changes reduce supply of glucose to the brain, compounding the intrinsic reduction in the brain's ability to metabolize glucose [7].…”

“…Neurovascular coupling and substrate supply were recently analyzed in neocortex in the CVN-AD Alzheimer's mouse model [16,[87][88][89][90][91]. This CVN-AD model (APPSwDI +/+/ mNos2−/−) of AD replicates extensively the histological and behavioral characteristics of the human disease including early onset of amyloid plaques by 12 weeks, phosphorylated tau by 24-36 weeks, and significant cell loss and behavioral changes by 36 weeks, replicating most human changes in pre-clinical and clinical aspects of AD (Fig.…”

“…In animal models we can also induce spreading depression events as a function of age by adding a focal potassium source onto the brain, to more adequately test enhanced blood flow (and indirectly substrate) supply to the brain in response to a severe metabolic demand. By testing these spreading depression events across age we can compare spontaneous aging neurovascular responses occurring in control animals to responses affected by degeneration in the transgenic animal model with Alzheimer's like stigmata [16,93]. During spreading depression events there is also significant calcium increase within neurons, which may be intrinsically damaging through loss of control of calcium-mediated signaling [1].…”

“…Vascular changes are also mirrored in a high incidence of stroke occurrence in Alzheimer's, further impeding the critical flow of substrate into the brain [6]. Altered neurovascular coupling occurs in mouse Alzheimer's models and in patients with both mild cognitive impairment [MCI] and overt AD [16,[31][32][33][34][35][36]. Many of these changes also occur with aging but are exaggerated in dementia syndromes [20].…”