Advances in the pathogenesis of Alzheimer's disease: focusing on tau-mediated neurodegeneration

Abstract

In addition to senile plaques and cerebral amyloid angiopathy, the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles (NFTs) represents another neuropathological hallmark in AD brain. Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability. When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former, tau is hyperphosphorylated and the level of the free tau fractions elevated. The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain. We have discussed the role of Aβ in AD in our previous review, this review focused on the recent advances in tau-mediated AD pathology, mainly including tau hyperphosphorylation, propagation of tau pathology and the relationship between tau and Aβ.

Figure 1

Tau-mediated neurodegeneration. Physiologically tau protein can bind and thereby stabilize microtubules (MTs). The attachment of tau to MT is regulated by its phosphorylation level. Phosphorylation of tau mediated by kinase (Cdk5, GSK3β, MARK and ERK2) may lead to the detachment of tau from MT and hereby cause MT depolymerization. Conversely, phosphatase (PP1, PP2A, PP2B and PP2C) will reduce the phosphorylation level of tau and restore the binding ability of tau for MT. Such equilibrium between the roles of kinases and phosphatases is disrupted under pathological condition, and increase in the kinase activity and decrease in the phosphatase activity will cause tau hyperphosphoryation. Hyperphosphorylated tau protein is misfolded and forms β-sheet-containing structure paired helical filaments (PHFs). These structure transitions will lead to more organized aggregates, and eventually develop neurofibrillary tangles (NFT) inside neurons. NFT will impair normal axonal transport, disrupt synaptic plasticity, and finally induce cell loss.