MECHANISMS OF NEUROFIBRILLARY DEGENERATION AND THE FORMATION OF NEUROFIBRILLARY TANGLES

Alzheimer disease (AD) has polyetiology. Independent of the etiology t he disease is characterized histopathologically by the intraneuronal a ccumulation of paired helical filaments (PHF), forming neurofibrillary tangles, neuropil threads and dystrophic neurites surrounding the ext racellular deposits of beta-amyloid in plaques, the second major lesio n. The clinical expression of AD correlates with the presence of neuro fibrillary degeneration; beta-amyloid alone does not produce the disea se clinically. Thus arresting neurofibrillary degeneration offers a pr omising key target for therapeutic intervention of AD. The major prote in subunit of PI-IF is the microtubule-associated protein tau. Tau in AD brain, especially PHF, is abnormally hyperphosphorylated and glycos ylated. With maturation, the tangles are increasingly ubiquitinated. L evels of tau and conjugated ubiquitin are elevated both in AD brain an d CSF. The AD abnormally phosphorylated tau (AD P-tau) does not promot e microtubule assembly, but on dephosphorylation its microtubule promo ting activity is restored to approximately that of the normal tau. The AD P-tau competes with tubulin in binding to normal tau, MAP1 and MAP 2 and inhibits their microtubule assembly promoting activities. Furthe rmore, the AD P-tau sequesters normal MAPs from microtubules. The asso ciation of AD P-tau with normal tau but not with MAP1 or MAP2 results in the formation of tangles of 3.3 +/- 0.5mm filaments. Deglycosylatio n of Alzheimer neurofibrillary tangles with endoglycosidase F/N-glycos idase F untwists the PHF resulting in tangles of thin filaments simila r to those formed by association between the AD P-tau and normal tau. Dephosphorylation or deglycosylation plus dephosphorylation but not de glycosylation alone restores the microtubule assembly promoting activi ty of tau. In vitro AD P-tau can be dephosphorylated by protein phosph atases PP-2B, PP-2A and PP-1 but not PP-2C and all the three tau phosp hatases are present in brain neurons. Tau phosphatase activity is decr eased by similar to 30% in AD brain. Inhibition of PP-2A and PP-1 acti vities in SY5Y neuroblastoma by 10 nM okadaic acid causes breakdown of microtubules and the degeneration of these cells. It is suggested (I) that a defect(s) in the protein phosphorylation/dephosphorylation sys tem(s) leads to a hyperphosphorylation of tau, (ii) that this altered tau causes disassembly of microtubules and consequently a retrograde n euronal degeneration; (iii) a pharmacological approach to AD is to enh ance the tau phosphatase activity; and (iv) that CSF tau and conjugate d ubiquitin levels are promising markers of AD brain pathology.