γ-Secretase, apolipoprotein E and cellular cholesterol metabolism

Genetic studies demonstrate that the 4 allele of the apolipoprotein (apo) E is a risk factor for late onset Alzheimer's disease (AD). Apo E is the major component of lipoprotein particles in the brain that mediate transport of cholesterol and other lipids between neurons and glial cells, indicating an implication of cerebral lipid metabolism in the pathogenesis of AD. In addition, apo E is also involved in the metabolism and aggregation of the amyloid β-peptide (Aβ) that derives from proteolytic processing of the amyloid precursor protein (APP) and is found in plaques of AD brains. The generation of Aβ involves sequential cleavages of APP by proteases called β- and γ-secretase. γ-Secretase is a high molecular weight protein complex containing presenilins as catalytically active subunits. Importantly, mutations in the genes of APP and the two homologous PS proteins are a major cause of familial early onset AD, indicating that the metabolism of APP and generation of Aβ play critical roles in the initiation of the disease. This review focuses on the functional relation of γ-secretase complexes and the metabolism of lipoproteins in the brain. It is hypothesized that γ-secretase activity is critically involved in cellular lipid homeostasis and that impaired lipid metabolism contributes to the pathogenesis of AD.