Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial

Abstract

Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Abeta(1-42) (where Abeta is amyloid beta-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I(2)(PP2A)) of PP2A (protein phosphatase 2A) at Asn(175) into N-terminal (I(2NTF)) and C-terminal (I(2CTF)) halves and their translocation from the neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I(2CTF) in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage of I(2)(PP2A)/SET offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.

Figure 1. Multifactorial nature, pivotal role, and mechanism of AD neurofibrillary degeneration

Neurofibrillary degeneration of the AD type is a product of multiple aetiological factors. Independent of the aetiology, neurofibrillary degeneration in AD and tauopathies involves abnormal hyperphosphorylation of tau and its occurrence in the neocortex is associated with dementia; neurofibrillary degeneration in the brainstem in progressive supranuclear palsy is associated with motor impairment. A cause of hyperphosphorylation of tau is a decrease in the activity of PP2A, a major tau phosphatase. Unlike normal tau, AD P-tau, instead of interacting with tubulin and promoting its assembly into microtubules, sequesters normal tau, MAP1 and MAP2, forming 200 000 g sedimentable oligomeric tau. The sequestration of normal MAPs disrupts microtubules and compromises axonal transport and consequently retrograde degeneration and dementia. The AD P-tau polymerizes into tangles of PHFs/SFs, which, unlike the cytosolic/oligomeric AD P-tau, interacts neither with tubulin nor with normal MAPs, but eventually obstructs further the microtubule network and axoplasmic flow as a space-occupying lesion.