Molecular Drivers of Regional and Cellular Vulnerability to Tau Accumulation and Neurodegeneration
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PROJECT SUMMARY Selective regional brain vulnerability is a fundamental feature in neurodegenerative diseases that must be deeply understood. In tauopathies, the brain areas where pathological tau accumulates are closely associated with regional atrophy and behavioral outcome. Our preliminary data in post-mortem human brain show that excitatory neurons are more vulnerable to tau accumulation than inhibitory neurons in Alzheimer’s disease but also other tauopathies such as FTD-MAPT, PSP and CBD. Using TRAP (Translating Ribosome Affinity Purification) and a tau mouse model P301S, we have investigated how specific brain regions and neuronal subtypes are vulnerable to tau pathology. We focused on two vulnerable brain regions—the prefrontal cortex (PFC) and hippocampus—and one resistant region, the primary visual cortex. Preliminary data suggest that MEF2C, an upstream regulator, plays a key role in mediating this regional vulnerability-resilience dichotomy. In this competitive renewal, we will investigate these mechanisms further, using both human post-mortem brain tissue, innovative in vitro assays with neuronal iPSC MEF2C-knock out (KO) and a MEF2C KO mouse model. Furthermore, we will investigate molecular differential regional vulnerability to tau pathology using state-of the-art integrated single-cell sequencing and spatial transcriptomics comparing typical Alzheimer’s disease and an atypical form, Posterior Cortical Atrophy, which starts tau pathology in the posterior areas in the brain rather than the medial temporal lobe in typical Alzheimer’s disease. In summary, this project will vertically advance our knowledge of a fundamental aspect of all neurodegenerative disorders by understanding the molecular drivers of cellular and regional susceptibility to accumulation of proteinopathies such as tauopathy.
