Signaling cascades of microtubule-associated protein Tau in Alzheimer's disease.

Abstract

Accumulation of neurofibrillary tangles (NFTs) in the neuronal cells is the predominant features of Alzheimer's diseases (AD) and other Tauopathies. Studies on molecular mechanism of human neurodegenerative disease shows that the substantial posttranslational modifications (PTMs) of Tau is essential for the conversion of monomeric soluble form into the aberrant insoluble aggregates in pathological condition. During pathogenesis of AD, Tau phosphorylation state is altered by the activation of various kinases and phosphates and eventually Tau become hyperphosphorylated. Hyperphosphorylated Tau detach from microtubules and aggregate intracellularly in affected neurons. This pathological Tau invades the subcellular organelles including mitochondria and leads to degeneration and cell death. Ageing is the crucial factor causing alteration in brain including, structural and functional role of Tau. Pathological Tau disrupts signaling cascades of mitochondria, energy-associated mechanism and this causes the elevation of oxidative stress in the neurons. Furthermore, hyperphosphorylated Tau also inhibits the mitophagy and autophagy-lysosomal pathway, resulting in the buildup of dysfunctional mitochondria in the affected neurons. This review highlights the major signaling cascades involved in Tau PTMs and its interlinked role in mitochondrial damage in aging population in AD.