Effects of amyloid precursor protein derivatives andoxidative stress on basal forebrain cholinergic systems inALZHEIMERS disease

Abstract

The dysfunction and degeneration of cholinergic neuronal circuits in the brain is aprominent feature of Alzheimers disease. Increasing data suggest that age-related oxidative stresscontributes to degenerative changes in basal forebrain cholinergic systems. Experimental studieshave shown that oxidative stress, and membrane lipid peroxidation in particular, can disruptmuscarinic cholinergic signaling by impairing coupling of receptors to GTP-binding proteins.Altered proteolytic processing of the β-amyloid precursor protein (APP) may contributeto impaired cholinergic signaling and neuronal degeneration in at least two ways. First, levels ofcytotoxic forms of amyloid β-peptide (Aβ) are increased ; Aβdamages and kills neurons by inducing membrane lipid peroxidation resulting in impairment ofion-motive ATPases, and glucose and glutamate transporters, thereby rendering neuronsvulnerable to excitotoxicity. The latter actions of Aβ may be mediated by4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation that covalently modifiesand inactivates the various transporter proteins. Subtoxic levels of Aβ can also suppresscholine acetyltransferase levels, and may thereby promote dysfunction of intact cholinergiccircuits. A second way in which altered APP processing may endanger cholinergic neurons is byreducing levels of a secreted form of APP which has been shown to modulate neuronalexcitability, and to protect neurons against excitotoxic, metabolic and oxidative insults. Mutationsin presenilin genes, which are causally linked to many cases of early-onset inherited Alzheimersdisease, may increase vulnerability of cholinergic neurons to apoptosis. The underlying mechanismappears to involve perturbed calcium regulation in the endoplasmic reticulum, which promotesloss of cellular calcium homeostasis, mitochondrial dysfunction and oxyradical production.Knowledge of the cellular and molecular underpinnings of dysfunction and degeneration ofcholinergic circuits is leading to the development of novel preventative and therapeuticapproaches for Alzheimers disease and related disorders.