Interaction of neurons and astrocytes underlies the mechanism of Aß-induced neurotoxicity.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the aggregation of amyloid ß-peptide (Aß) into ß-sheet-rich fibrils. Although plaques containing Aß fibrils have been viewed as the conventional hallmark of AD, recent research implicates small oligomeric species formed during the aggregation of Aß in the neuronal toxicity and cognitive deficits associated with AD. We have demonstrated that oligomers, but not monomers, of Aß40 and Aß42 were found to induce calcium signalling in astrocytes but not in neurons. This cell specificity was dependent on the higher cholesterol level in the membrane of astrocytes compared with neurons. The Aß-induced calcium signal stimulated NADPH oxidase and induced increased reactive oxygen species (ROS) production. These events are detectable at physiologically relevant concentrations of Aß. Excessive ROS production and Ca²âº overload induced mitochondrial depolarization through activation of the DNA repairing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and opening mitochondrial permeability transition pore (mPTP). Aß significantly reduced the level of GSH in both astrocytes and neurons, an effect which is dependent on external calcium. Thus Aß induces a [Ca²âº]c signal in astrocytes which could regulate the GSH level in co-cultures that in the area of excessive ROS production could be a trigger for neurotoxicity. The pineal hormone melatonin, the glycoprotein clusterin and regulation of the membrane cholesterol can modify Aß-induced calcium signals, ROS production and mitochondrial depolarization, which eventually lead to neuroprotection.