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

Abstract

Alzheimer's disease is a chronic degenerative disorder characterized by the intracellular accumulation of “paired helical filaments” consisting of highly phosphorylated tau and by extracellular deposits of aggregated Aβ-peptide. Furthermore, neurodegeneration in Alzheimer's disease is associated with the appearance of neuritic growth profiles that are aberrant with respect to their localization, morphological appearance, and composition of cytoskeletal elements. 2 During early stages of Alzheimer's disease, a variety of growth factors and mitogenic compounds 10,12,15,16,18,32 are elevated. Most of these factors mediate their cellular effects through activation of the p21 ras-dependent mitogen-activated protein kinase cascade, a pathway that is also involved in the regulation of expression and post-translational 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 ras associated with paired helical filament formation and Aβ-deposits. 17 However, the question arises as to whether induction of p21 ras and the downstream mitogen-activated protein kinase cascade is an early event with rather primary importance in the pathogenetic chain or simply occurs as a cellular response to neurodegeneration. 29 The present study shows that expression of p21 ras is clearly elevated in very early stages of the disease, preceding both neurofibrillary pathology and formation of Aβ.