Cholesterol´s role in membrane organization and nicotinic acetylcholine receptor function: Implications for aging and Alzheimer's disease

Abstract

Biological membranes are complex entities composed of various molecules exhibiting lateral and transbilayer lipid asymmetries, along with a selective spatial distribution of different membrane proteins. This dynamic orchestration is crucial for proper physiological functions, undergoes changes with aging, and is disturbed in several neurological disorders. In this review, we analyze the impact of disruption in this equilibrium on physiological aging and the onset of pathological conditions. Alzheimer´s disease (AD) is a multifactorial neurodegenerative disorder in the elderly, characterized by the increased presence of the Aβ peptide, which supports the amyloid hypothesis of the disease. However, AD also involves a progressive loss of cholinergic innervation, leading to the cholinergic hypothesis of the disease. Nicotinic acetylcholine receptors (nAChRs) are transmembrane proteins, and Aβ peptides, their oligomeric and fibrillar species, which increase in hydrophobicity as they develop, interact with membranes. Therefore, a membrane hypothesis of the disease emerges as a bridge between the other two. Here, we discuss the impact of the membrane environment, through direct or indirect mechanisms, on cholinergic signaling and Aβ formation and subsequent incorporation into the membrane, with a special focus on the crucial role of cholesterol in these processes.