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

Abstract

AbstractBackgroundAlzheimer’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.MethodHuman 0N4R Tau (wild type) was expressed in touch receptor neurons through single‐copy gene insertion. Mutations were introduced into the single‐copy tau transgene through CRISPR‐Cas9 genome editing, including T231E and T231A, to mimic phosphorylation and phospho‐ablation of a commonly observed pathological epitope, respectively, and K274/281Q, to mimic disease‐associated lysine acetylation. We then assessed their impact on age‐dependent response to light touch, neurodegeneration, and mitochondrial parameters such as abundance, morphology, trafficking, and turnover, using fluorescent biosensors including mito‐mKeima.ResultUnlike existing tau overexpression models, C. elegans single‐copy expression of wild type human tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM‐mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. Remarkably, the PTM‐mimetics selectively impaired mitophagy following mitochondrial oxidative stress, but had no effect on macroautophagy, and furthermore reduced mitolysosomal trafficking.ConclusionSingle copy expression limits pathological phenotypes to strains expressing disease‐associated Tau mutants. In addition to overt pathology, these mutants eliminate oxidative stress‐induced mitophagy and reduce trafficking of mitolysosomes. Our findings highlight a selective mechanism through which disease‐associated Tau PTMs may suppress compensatory responses to mitochondrial stress that occur with age and provide a new perspective into the pathogenic mechanisms underlying AD.