Tau Phosphorylation Research
Aggregation of hyperphosphorylated tau characterizes neuropathological lesions in diseases like AD. Recent studies support that disease-associated changes in soluble tau, including phosphorylation, occur relatively early and are involved in the induction of neuronal death.
Scientists caution, though, that while numerous reports have produced a huge amount of information about the activities of specific kinases on tau, the “identities of the true physiological and pathological kinases in vivo remain unknown.” Several strategies to mitigate tau phosphorylation, including disaggregation of tau inclusions and tau immunotherapy, can be pursued investigators have remarked.
Phosphorylation reduction through inhibition of specific protein kinases, however, remains of interest to many scientists as a viable strategy. Inhibition of proline-directed protein kinases such as glycogen synthase kinase-3 (GSK-3) and cyclin dependent kinase-5 (CDK-5) have been studied in transgenic animal studies. Other candidate kinases impacting tau hyperphosphorylation that may serve as potential drug targets include the extracellular signal-regulated kinase ERK2, casein kinase 1.
GSK-3beta has been implicated in multiple cellular processes and linked with pathogenesis of and neuronal loss in several neurodegenerative diseases including Parkinson and Huntington diseases. Studies have shown that the enzyme’s overexpression in transgenic mouse models results in increased tau phosphorylation and deficits in spatial learning. Inhibition of GSK-3beta activity leads to neuroprotective effects, decreased amyloid-beta production, and a reduction in tau hyperphosphorylation.
CDK-5, on the other hand, is required for the development of the central nervous system through regulation of neuronal migration. One of its activators, p25, is increased in AD brains where p25 and CDK-5 are co-localized with neurofibrillary tangles.
Several animal models have shown a correlation of p25/CDK-5 activities with tau phosphorylation. Overexpression of p25/CDK-5 in neuronal cultures not only leads to tau phosphorylation but also cytoskeletal abnormalities and neurodegeneration.