Rescuing neurovascular coupling to protect neuronal plasticity and cognition - Summary Growing evidence points towards the contribution of altered brain microcirculation to cognitive impairment and dementia observed in Alzheimer’s disease (AD) and AD-related dementia (ADRD). Yet, the lack of approaches to image the small cerebrovasculature and investigate its function has hampered our progress in understanding the pathological sequence of vascular cognitive impairment and dementia (VCID). The earliest signs of AD and VCID in patients and mouse models typically involve deficits in spatial and short-term memory—cognitive functions that are critically sustained by synaptic plasticity in the hippocampus. Neurons have limited energy reserves and thus rely on a “just-in-time” neurovascular coupling (NVC) strategy in which active regions signal to the microvasculature to locally dilate and increase local blood flow. Patients and mouse models of AD or CADASIL, a monogenic archetypal form of VCID, show an early deterioration in NVC. Our previous studies have identified a molecular defect at play in capillary endothelial cells and developed a therapeutic approach that acutely restores NVC in the mouse model of AD and CADASIL. Specifically, we found that systemic injection of phospholipid PIP2 is sufficient to rescue neurovascular deficits by enabling Kir2.1 channels to act as sensors of increases in external K+—a product of neuronal activity—and transduce this into a vasodilator electrical signal that rapidly propagates to upstream arterioles, driving vasodilation to produce local hyperemia. Our multidisciplinary team, with complementary expertise in cutting-edge imaging of brain microcirculation and synaptic plasticity underlying learning and memory processes, will test the hypothesis that NVC restoration will mitigate the synaptic plasticity deterioration in the hippocampus, and its behavioral consequences, observed in AD. We further propose to investigate and compare these functions in CADASIL, a vascular driven form of ADRD. To attain this goal, we will advance our PIP2-based strategy to chronically restore NVC in AD and CADASIL models, and assess the treatment efficiency by developing innovative imaging approaches ex vivo, with a novel intact capillary-arteriolar (CaPA) preparation established by our group, and in vivo using implanted graded-index (GRIN) lenses combined with 2-photon microscopy to investigate NVC in the hippocampus. Ultimately, we will measure the effect of NVC rescue on hippocampal synaptic plasticity deterioration caused by AD and CADASIL conditions, and use contextual fear conditioning as a behavioral readout. Completing this study will help elucidate the mechanisms linking NVC dysfunction to dementia in AD/ADRDs, and NVC restoration as a potential therapy. The proposed work has the potential to provide a paradigm-shifting view on how brain microcirculation sustains learning and memory processes.
