Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach

Neurofibrillary degeneration is a key histopathological brain lesion of Alz heimer disease (AD) and related neurodegenerative disorders such as frontot emporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), common ly referred to as tauopathies. Microtubule associated protein (MAP) tau, wh ich is a major MAP of a normal mature neuron is abnormally hyperphosphoryla ted in tauopathies and is the major protein subunit of paired helical filam ents (PHF)/straight filaments (SF) which accumulate in the soma (as neurofi brillary tangles) and dystrophic neurites (as neuropil threads and as dystr ophic neurites surrounding the beta-amyloid core in neuritic plaques in AD) of the affected neurons. Unlike normal tau which stimulates assembly and s tabilizes microtubules, the abnormally hyperphosphorylated tau inhibits ass embly and disrupts microtubules. The abnormally hyperphosphorylated tau com petes with tubulin/microtubules in associating with normal tau, MAP1 and MA P2. This sequestration of normal MAPs by the abnormal tau results in the br eakdown of the microtubules. The association of the abnormal tau with norma l tau and not with MAP1 or MAP2 results in the formation of tangles of tau filaments. All these toxic properties of the abnormally hyperphosphorylated tau are eliminated by its enzymatic dephosphorylation. Activities of phosp hoseryl/phosphothreonyl protein phosphatases (PP)-2A and PP-1 which can dep hosphorylate the abnormal tau to a normal-like state are compromised in AD brain. Dephosphorylation by PP-2A and PP-2B and to a lesser extent by PP-1 restores the normal microtubule assembly promoting activity in AD P-tau in vitro. Neurofibrillary tangles of PHF isolated from AD brain are also disso ciated on in vitro dephosphorylation with PP-2A, and the tau released by th is treatment can stimulate microtubule assembly. Thus, it appears that the abnormal hyperphosphorylation of tau leads to neurodegeneration through bre akdown of the microtubule network and that the abnormal tau on association with normal tau forms neurofibrillary tangles of tau filaments i.e. PHF/SF. Increase in tau phosphatase activity is a promising approach to inhibit ne urofibrillary degeneration and thereby the diseases characterized by this l esion.