Oxidative stress and death domain proteins in Alzheimer's disease

Abstract

Signal-transduction pathways in the central nervous system provide key mechanisms for cellular responses to environmental stresses. Oxidative stresses are operative in the aging brain with infarction and Alzheimer's disease (AD). Mitogen-activated protein (MAP) kinases mediate these inputs to downstream targets, such as transcription factors. The result is either regeneration and protection, or cell death. AD, a multifactorial disease, results in death of selectively vulnerable neuronal subpopulations. Etiologic factors, including Aβ-oxidative stress, exert toxic effects through the MAP kinase signal transduction pathway. MAP kinases, including ERKs and stress-activated protein kinases especially c-Jun, N-terminal kinases (JNKs) and P38, are prime candidates for activation of c-Jun. Both ERKs and JNKs cause tau hyperphosphorylation potentially contributing to neurofibrillary tangle formation. Differentially expressed in neoplastic and non-neoplastic tissue (DENN)/mitogen-activated kinase activating death domain protein (MADD), a GDP/GTP exchange factor under basal conditions, interacts with JNK under Aβ stress through its JNK binding domain. As a death domain (DD)-bearing protein, DENN/MADD also interacts with other DD-proteins such as TNFR1. Our hypothesis is that DENN/MADD plays a potentially pivotal role in AD, in the cell death/survival process, via JNK. At a chronic level, DENN/MADD may modulate activation of the TNFR1 pathway by the pro-inflammatory cytokine, tumor necrosis factor-α, released by Aβ-activated macrophages and by JNK induction of FAS ligand which promote cell death via the FAS/TNFR pathway. © 2003 Elsevier Science B.V. All rights reserved.