Elevated expression of p21(ras) is an early event in Alzheimer's disease and precedes neurofibrillary degeneration

Alzheimer's disease is a chronic degenerative disorder characterized by the intracellular accumulation of "paired helical filaments" consisting of hig hly phosphorylated tau and by extracellular deposits of aggregated A beta-p eptide. Furthermore, neurodegeneration in Alzheimer's disease is associated with the appearance of neuritic growth profiles that are aberrant with res pect to their localization, morphological appearance, and composition of cy toskeletal elements.(2) During early stages of Alzheimer's disease, a varie ty of growth factors and mitogenic compounds(10,12,15,16,18,32) are elevate d. Most of these factors mediate their cellular effects through activation of the p21(ras)-dependent mitogen-activated protein kinase cascade, a pathw ay that is also involved in the regulation of expression and post-translati onal modification of the amyloid precursor protein and tau protein.(7,11,13 ,14,19,20,22,31) We previously reported on the elevated expression of p21(r as) associated with paired helical filament formation and A beta-deposits.( 17) However, the question arises as to whether induction of p21(ras) and th e downstream mitogen-activated protein kinase cascade is an early event wit h rather primary importance in the pathogenetic chain or simply occurs as a cellular response to neurodegeneration.(29) The present study shows that e xpression of p21(ras) is clearly elevated in very early stages of the disea se, preceding both neurofibrillary pathology and formation of A beta. (C) 1 999 IBRO, Published by Elsevier Science Ltd.