MOLECULAR DISSECTION OF THE PAIRED HELICAL FILAMENT

Abundant neurofibrillary tangles, neuropil threads and plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease wher e their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major fi brous component. Recent work has shown that PHFs are composed of the m icrotubule-associated protein tau in a hyperphosphorylated state. PHF- tau is hyperphosphorylated on six adult brain tau isoforms. As a conse quence, tan is unable to bind to microtubules and is believed to self- assemble into the PHF. Current evidence suggests that protein kinases or protein phosphatases with a specificity for serine/threonine-prolin e residues play an important role in the hyperphosphorylation of tau. Candidate protein kinases include mitogen-activated protein kinase, gl ycogen synthase kinase-3 and cyclin-dependent kinase 5, whereas the tr imeric form of protein phosphatase 2A is a candidate phosphatase.