Effects of amyloid precursor protein derivatives and oxidative stress on basal forebrain cholinergic systems in Alzheimer's disease

The dysfunction and degeneration of cholinergic neuronal circuits in the br ain is a prominent feature of Alzheimer's disease. Increasing data suggest that age-related oxidative stress contributes to degenerative changes in ba sal forebrain cholinergic systems. Experimental studies have shown that oxi dative stress, and membrane lipid peroxidation in particular, can disrupt m uscarinic cholinergic signaling by impairing coupling of receptors to GTP-b inding proteins. Altered proteolytic processing of the beta-amyloid precurs or protein (APP) may contribute to impaired cholinergic signaling and neuro nal degeneration in at least two ways. First, levels of cytotoxic forms of amyloid beta-peptide (A beta) are increased; A beta damages and kills neuro ns by inducing membrane lipid peroxidation resulting in impairment of ion-m otive ATPases, and glucose and glutamate transporters, thereby rendering ne urons vulnerable to excitotoxicity. The latter actions of A beta may be med iated by 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidat ion that covalently modifies and inactivates the various transporter protei ns. Subtoxic levels of A beta can also suppress choline acetyltransferase l evels, and may thereby promote dysfunction of intact cholinergic circuits. A second way in which altered APP processing may endanger cholinergic neuro ns is by reducing levels of a secreted form of APP which has been shown to modulate neuronal excitability, and to protect neurons against excitotoxic, metabolic and oxidative insults. Mutations in presenilin genes, which are causally linked to many cases of early-onset inherited Alzheimer's disease, may increase vulnerability of cholinergic neurons to apoptosis. The underl ying mechanism appears to involve perturbed calcium regulation in the endop lasmic reticulum, which promotes loss of cellular calcium homeostasis, mito chondrial dysfunction and oxyradical production. Knowledge of the cellular and molecular underpinnings of dysfunction and degeneration of cholinergic circuits is leading to the development of novel preventative and therapeuti c approaches for Alzheimer's disease and related disorders. (C) 1999 ISDN. Published by Elsevier Science Ltd. All rights reserved.