Abstract
Genetic studies demonstrate that the 4 allele of the apolipoprotein (apo) E is a risk factor for late onset Alzheimers 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.
Keywords: Secretase, Alzheimer disease, membane lipids, lipoproteins, Cholesterol Metabolism, BACE2, mutations, glial cells, Kunitz-Protease-Inhibitor
Current Alzheimer Research
Title: γ-Secretase, Apolipoprotein E and Cellular Cholesterol Metabolism
Volume: 9 Issue: 2
Author(s): Jochen Walter
Affiliation:
Keywords: Secretase, Alzheimer disease, membane lipids, lipoproteins, Cholesterol Metabolism, BACE2, mutations, glial cells, Kunitz-Protease-Inhibitor
Abstract: Genetic studies demonstrate that the 4 allele of the apolipoprotein (apo) E is a risk factor for late onset Alzheimers 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.
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Cite this article as:
Walter Jochen, γ-Secretase, Apolipoprotein E and Cellular Cholesterol Metabolism, Current Alzheimer Research 2012; 9 (2) . https://dx.doi.org/10.2174/156720512799361583
DOI https://dx.doi.org/10.2174/156720512799361583 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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