CAA, Tau and Neurodegeneration - Summary Alzheimer's disease (AD), the most common form of dementia, is characterized by the extracellular deposition of parenchymal β-amyloid (Aβ), intracellular accumulation of tau as neurofibrillary tangles (NFTs), neuronal cell loss, and significant inflammation. Cerebral amyloid angiopathy (CAA), the accumulation of amyloid in arterial walls, occurs in over 85% of AD cases, positioning CAA as one of the strongest vascular contributors to age-related cognitive decline. CAA has been associated with an active immune response and perivascular deposition of hyperphosphorylated tau; yet these three pathological entities have never been linked in relation with cognitive decline. Our recent studies have contributed to understanding the pathogenesis of CAA and the preponderant roles that tau, reactive astrocytes and the complement system could play in the synaptotoxicity associated with vascular amyloid deposition. Considering that there is still no clear understanding of the molecular and cellular mechanisms and targets that underlie the contribution of CAA to neurodegeneration and dementia, the main hypothesis of this renewal is that in CAA, there is a distinct group of neurotoxic C3+ reactive astrocytes which significantly contribute to disease pathogenesis. Moreover, we propose that reducing tau expression in these astrocytes leads to neuroprotection by downregulating the complement pathway, resulting in reduced glial reactivity and synaptic loss. By introducing a series of biochemical, molecular, histological, electrophysiological, behavioral, imaging, and transcriptomics-based strategies together with novel mouse models and human postmortem tissue, this proposal will 1. evaluate the neuroprotective effect of blocking C3+ astrocytes conversion on CAA pathogenesis in vivo, 2. test whether cell-specific ablation of Mapt rescues disease-associated phenotypes in a CAA model in vivo and 3. determine whether reactive astrocytes associated with vascular amyloid are distinct from astrocytes associated with parenchymal amyloid deposits in CAA/AD patients, by integrating spatial whole transcriptomic with single nucleus RNA sequencing. The proposed studies will continue providing a platform for the understanding the mechanism(s) contributing to neurodegeneration associated with CAA. Information gained from these studies may lead to the development of effective therapeutics not only for CAA and AD, but also for a number of neurodegenerative diseases characterized by the vascular accumulation of amyloid peptides.
