Mediators of tau phosphorylation in the pathogenesis of Alzheimer's disease

The need for disease-modifying drugs for Alzheimer's disease has become increasingly important owing to escalating disease prevalence and the associated socio-economic burden. Until recently, reducing brain amyloid accumulation has been the main therapeutic focus; however, increasing evidence suggests that targeting abnormal tau phosphorylation could be beneficial. Tau is phosphorylated by several protein kinases and this is balanced by dephosphorylation by protein phosphatases. Phosphorylation at specific sites can influence the physiological functions of tau, including its role in binding to and stabilizing the neuronal cytoskeleton. Aberrant phosphorylation of tau could render it susceptible to potentially pathogenic alterations, including conformational changes, proteolytic cleavage and aggregation. While strategies that reduce tau phosphorylation in transgenic models of disease have been promising, our understanding of the mechanisms through which tau becomes abnormally phosphorylated in disease is lacking.