Fig. 3: Phosphorylation level of tau regulates the integrity of the neuronal cytoskeleton.
From: Amyloid-β and Tau in Alzheimer’s disease: pathogenesis, mechanisms, and interplay
Under physiological conditions, there is a balance between the activity of kinases and phosphatases that regulates the phosphorylation level of tau. Due to this balanced activity, tau remains attached to the cytoskeleton and then promotes the assembly and formation of microtubules. This bolsters the structural integrity of the neuronal cytoskeleton. On the contrary, under pathological conditions, kinase reactions are more favored (perhaps due to the increased activity or protein levels of kinases), leading to the hyperphosphorylation of tau. Hyperphosphorylated tau detaches from the cytoskeleton, causing the depolymerization of microtubules, thus impairing the neuronal cytoskeleton. Ultimately, hyperphosphorylated tau proteins self-assemble as tau filaments (paired helical filaments or straight filaments); then, they spread throughout the brain, forming NFTs. These NFTs cause neuronal structural damage or induce neurodegeneration, leading to dementia and cognitive damage.
