Multimodal approaches to study the isoform-specific role of FynT tyrosine kinase in association with tau pathology in alzheimer's disease and related tauopathies

• Main Author: Low, Clara Ying Bei
• Other Authors: Valerie Lin
• Format: Thesis-Master by Research
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/152838
• Institution: Nanyang Technological University

Accumulating evidence has shown the involvement of Fyn tyrosine kinase in Alzheimer’s disease (AD), in particular in the formation of neurofibrillary tangles which is one of the hallmarks of AD. Our preliminary data showed that FynT isoform directly phosphorylated tau at Tyrosine18. The data also suggested cascade of indirect phosphorylation at serine and threonine sites of tau, and accumulation of tau protein, which may lead to neurofibrillary tangle formation. Furthermore, our group previously showed that FynT expression is selectively upregulated in the AD neocortex, and is associated with neurofibrillary tangle formation and reactive astrogliosis. Hence, we hypothesize that FynT isoform may play critical roles in mediating tau pathology and neuroinflammation in neurodegenerative diseases, not exclusive to AD. Our specific aims are (1) to determine FynT and FynB isoform expression in association with tau pathology in AD and non-AD neurodegenerative dementias, and (2) to determine the role of FynT in tau pathology and neuroinflammation using transgenic mouse models. It was found that the selective upregulation of FynT but not of FynB expression in AD and LBD (Lewy Body Dementia) neocortex, was correlated with cognitive impairment, neuropathological features and neuroinflammation. Consistently, selective upregulation of FynT expression shown in our old-aged (≥ 6mo) Tau (P301S) mice overexpressing the human tau transgene, was correlated with tau pathology. Severe neuroinflammation and synaptic degeneration were also detected in these mice. Knocking out FynT in Tau mice (Double Transgenic mice) was able to reverse tau pathology, neuroinflammation and synaptic degeneration during disease progression. The male mice exhibited more severe disease pathogenesis and better disease amelioration than the females, suggesting gender differences. Our data provided strong evidence that the pathogenic FynT isoform could be a potential therapeutic target for AD and tauopathy diseases.