The Role of Alzheimer’s disease relevant Tau modifications in Neurodegeneration and Mitochondrial dysfunction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose pathological hallmarks include intraneuronal neurofibrillary tangles (NFTs) composed of the microtubule‐associated protein Tau. Tau isolated from AD brain exhibits abnormally high levels of post‐translational modifications (PTMs) including phosphorylation and acetylation at specific epitopes that increase with disease severity and age. In addition, mitochondrial dysfunction is an early feature of AD, and abnormal, toxic tau PTMs may contribute to disease pathogenesis. A major bottleneck in understanding the mechanisms behind the neurotoxicity of pathological forms of Tau is the lack of genetically tractable models that can recapitulate the effects of Tau PTMs in a short time frame without artifacts associated with Tau overexpression.