Role of 4R tau in astrocyte-mediated neuronal toxicity and the progression of neurodegenerative disease
Date of Award
Doctor of Philosophy (PhD)
The microtubule-binding protein tau is associated with neurodegenerative diseases, including Alzheimer’s disease, progressive supranuclear palsy, and a subset of frontotemporal dementias. In these tauopathies, tau becomes hyperphosphorylated and forms intracellular neurofibrillary tau tangles, contributing to synaptic dysfunction, neuronal death, and severe astrogliosis. Tau can be classified as having a 3-repeat (3R) or 4-repeat (4R) structure, resulting from alternative splicing of exon 10 within the MAPT gene. While the higher deposition of 4R tau characterizes many primary tauopathies, the role of 4R tau in neurodegenerative disease pathogenesis remains unclear. To investigate the role of tau isoforms in disease, we created tau splicing antisense oligonucleotides (ASOs) that alter the ratio of 3R:4R tau. In earlier studies, ASO-induced preferential expression of 4R tau in a murine model increased both seizure severity and phosphorylated tau deposition. The absence of overt neuronal or synaptic loss to explain the observed 4R tau-mediated phenotype in mice prompted a closer examination of astrocytes, which also exhibit pathologic tau deposition in tauopathies. Human tau (hTau) expressing mice treated with a 3R to 4R tau splicing AO exhibited co-localization of 4R tau with reactive astrocytes and increased expression of pan-reactive and neurotoxic genes. In primary murine astrocytes, increased astrocytic 4R tau levels provoked a similar morphological change, neurotoxic genetic profile, a vulnerability to oxidative damage, and a decreased ability to buffer glutamate. These results were replicated in a human iPSC model, and healthy neurons exhibited a higher firing frequency and hyper-synchrony when cultured with 4R tau-expressing human iPSC-derived astrocytes. Neurons cultured with 4R tau expressing astrocytes also exhibited higher levels of cytotoxicity. Furthermore, lowering 4R tau expression decreased levels of cytotoxicity in both models and prevented neuronal hyper-excitability and death when cultured with human astrocytes treated to reduce tau levels. These findings support a novel pathway of astrocytic 4R tau that mediates reactivity and dysfunction and suggest that astrocyte-targeted therapeutics against 4R tau may play an important role in mitigating neurodegenerative disease progression.
Chair and Committee
Timothy M. Miller
Albert A. Davis
Ezerskiy, Lubov Alexandra, "Role of 4R tau in astrocyte-mediated neuronal toxicity and the progression of neurodegenerative disease" (2021). Arts & Sciences Electronic Theses and Dissertations. 2563.