Cholesterol and Amyloid-β: Evidence for a Cross-Talk between Astrocytes and Neuronal Cells

Accumulating data support the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-beta (A beta) peptides in the brain. Changes in the neuronal production of A beta have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that A beta may serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that A beta(42) exerts an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Accordingly, we also show that ABCA1 expression is reduced in the brain of A beta PP/PS1 transgenic mice. These results provide a biological function for A beta peptides and may help to define the pathogenic relationship between cholesterol metabolism in brain and AD.