1. Nat. Rev. Neurol. doi:10.1038/nrneurol.2015.225
Figure 5 Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches
Figure 5 | Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches. Abnormal hyperphosphorylation of tau is the common key step in neurofibrillary degeneration in Alzheimer disease (AD) and other tauopathies. Activity of PP2A, the main regulator of tau phosphorylation, is compromised, at least in AD, Down syndrome and Guam parkinsonism–dementia brains. Nevertheless, both inhibition of tau protein kinase and enhancement of protein phosphatase 2A (PP2A) activity are potential therapeutic approaches. Promotion of O-GlcNAcylation, which negatively regulates hyperphosphorylation of tau, is an alternative strategy. Sequestration of normal microtubule-associated proteins (MAPs) by hyperphosphorylated tau (P-tau) can be prevented by inhibiting tau hyperphosphorylation or neutralizing the binding with a compound. Microtubule-stabilizing compounds can have beneficial therapeutic effects by making stability of the microtubule network independent from tau. Tau pathology can be reduced by inhibiting tau hyperphosphorylation, dissociating tau aggregates, or tau immunization. Finally, pharmacological promotion of neuroregeneration by enhancing neurogenesis and neuronal plasticity has produced not only rescue of cognitive impairment but also reduction of both tau and amyloid-β pathologies in a transgenic mouse model of AD.
Iqbal, K. et al. (2015) Tau and neurodegenerative disease: the story so far
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