Vascular Mechanisms of Dementia: Cell-Type Specific Therapeutic and Imaging Strategies

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ABSTRACT: Neuropathological studies in dementia frequently show mixed features including classical Alzheimer's hallmarks, cerebral amyloid angiopathy (CAA), microhemorrhages, and microinfarcts, highlighting the complexity and importance of vascular mechanisms in neurodegeneration. The precise mechanisms leading to CAA, microvascular degeneration, and dysregulated cerebral blood flow (CBF) are poorly understood. The cellular constituents of blood vessels include endothelial and mural cells (smooth muscle cells or pericytes), all of which have critical roles in CBF regulation and blood-brain barrier maintenance. While these cells are prominently affected in neurodegeneration, there are currently no specific therapeutic strategies for protecting them. A key objective of this application is to develop innovative strategies to therapeutically target and image the various vascular cellular components to improve our understanding of mechanisms leading to dementia. Specifically, we aim to complete proof-of-concept studies with a focus on potential mechanisms of cytotoxicity mediated by iron metabolism/reactive oxygen species (ROS) that may lead to microvascular degeneration. We aim to develop and test compounds that can preferentially target brain pericytes, smooth muscle cells, and endothelial cells with the goal of reducing intracellular free iron and ROS toxicity and ameliorating microvascular degeneration. These cell-type specific compounds will also be tested to determine their potential to be used as probes for deep tissue brain imaging in preclinical studies. To achieve this, we have assembled a multidisciplinary team at the interface of neurovascular biology and chemistry and propose a comprehensive set of experiments that combine intravital brain microscopy, chemical synthesis, single-cell transcriptomics, and animal models of CAA and microvascular pathology. This project has the potential for identifying targets and strategies for ameliorating microvascular degeneration that could significantly impact our mechanistic understanding and therapeutic approaches for vascular dementia.