Understanding cellular architecture of the neurovascular unit and its function in the whole mouse brain

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Abstract Alzheimer’s disease (AD) is characterized by steep cognitive decline especially affecting learning and memory and has become a prominent public health concern driven by an increasing aging population. Prior research pinpointed accumulations of toxic cellular wastes such as amyloid beta (Aβ) as a primary pathophysiological hallmark in AD. Vascular disorders, which affect the brain’s ability to clear metabolic wastes and supply energy to neurons, have long been implicated in AD pathology. Microvessels which form complex networks provide large surface areas as a main interface between blood supply and brain tissues. Moreover, pericytes ensheathe microvessels allowing them to regulate blood flow and permeability. Emerging evidence suggests that the degeneration of microvessels and pericytes has been frequently observed in AD patients and animal models of AD. Moreover, Aβ accumulation and degeneration of vascular networks in AD occur in different brain regions at different rates across the whole brain. While strong evidence of the harmful interactions between Aβ accumulation and neurovascular function in AD exists, whether microvessel and pericyte injury occurs prior to Aβ accumulation and how interactions of Aβ with microvessels and pericytes change over time across different brain regions remains unclear. To discover this and more fully understand brain regional vulnerabilities, temporal affectations, and their consequences to brain function, we need to examine the quantitative distribution of microvessels and pericytes upon Aβ insults in relation to AD related behavioral changes. Therefore, we propose a two part hypothesis to examine the brain-wide changes of microvessels and pericyte populations in correlation with the emergence of Aβ accumulation in 5xFAD mice. SA1 will focus on the hypothesis that degeneration of microvessels occurs prior to Aβ accumulation and cognitive deficit while SA2 will test a hypothesis that degeneration of pericytes precede Aβ accumulation as the disease progresses. Both methods will utilize cutting- edge clearing and 3D immunolabeling, high-resolution light sheet fluorescent microscopy imaging, and advanced computational analysis to generate a first of its kind vascular/pericyte whole brain atlas in an AD mouse model with further analysis to resolve the interactions of microvessels/pericytes with Aβ paired with behavioral testing to assess cognitive deficits at the presymptomatic and early symptomatic stages of AD.