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 brain is a prominent feature of Alzheimer's disease. Increasing data suggest that age-related oxidative stress contributes to degenerative changes in basal forebrain cholinergic systems. Experimental studies have shown that oxidative stress, and membrane lipid peroxidation in particular, can disrupt muscarinic cholinergic signaling by impairing coupling of receptors to GTP- binding proteins. Altered proteolytic processing of the β-amyloid precursor protein (APP) may contribute to impaired cholinergic signaling and neuronal degeneration in at least two ways. First, levels of cytotoxic forms of amyloid β-peptide (Aβ) are increased; Aβ damages and kills neurons by inducing membrane lipid peroxidation resulting in impairment of ion-motive ATPases, and glucose and glutamate transporters, thereby rendering neurons vulnerable to excitotoxicity. The latter actions of Aβ may be mediated by 4- hydroxynonenal, an aldehydic product of membrane lipid peroxidation that covalently modifies and inactivates the various transporter proteins. Subtoxic levels of Aβ can also suppress choline acetyltransferase levels, and may thereby promote dysfunction of intact cholinergic circuits. A second way in which altered APP processing may endanger cholinergic neurons 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 underlying mechanism appears to involve perturbed calcium regulation in the endoplasmic reticulum, which promotes loss of cellular calcium homeostasis, mitochondrial 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 therapeutic approaches for Alzheimer's disease and related disorders.