Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer’s disease and Lewy body dementias

Cumulative data suggest the involvement of Fyn tyrosine kinase in progression of Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also frequently found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the postmortem neocortex of patients with AD, as well as those having one of the two main subgroups of LBD: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β-amyloid and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human postmortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings point to FynT being an important mediator of disease progression in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.