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Mechanisms of Disease: new therapeutic strategies for Alzheimer's disease—targeting APP processing in lipid rafts

Nature Clinical Practice Neurology volume 3, pages 374–382 (2007)Cite this article

Abstract

Alzheimer's disease (AD) is the most common cause of age-related dementia. Pathologically, AD is characterized by the deposition in the brain of amyloid-β peptides derived from proteolysis of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. A growing body of evidence implicates cholesterol and cholesterol-rich membrane microdomains in amyloidogenic processing of APP. Here, we review recent findings regarding the association of BACE1, γ-secretase and APP in lipid rafts, and discuss potential therapeutic strategies for AD that are based on knowledge gleaned from the membrane environment that fosters APP processing.

Key Points

  • Cholesterol has been an important focus of research into Alzheimer's disease, but controversy has emerged regarding the therapeutic value of lowering cholesterol as a protective measure against this disease

  • Certain aspects of cholesterol metabolism regulate amyloid-β production through direct modulation of amyloid precursor protein (APP) processing by secretases

  • β-Site APP cleaving enzyme 1, γ-secretase and APP C-terminal fragments are localized in lipid rafts, which are membrane microdomains rich in cholesterol and sphingolipids

  • Amyloidogenic processing of APP occurs in lipid raft domains, and experimental manipulations that disturb the integrity of lipid rafts affect amyloid-β production

  • Compartmentalization of APP C-terminal fragments and secretases offers unique opportunities to selectively target APP processing

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Figure 1: Schematic diagram of intracellular amyloid precursor protein trafficking in a model cell
Figure 2: Distribution of amyloid precursor protein and secretases in membrane microdomains
Figure 3: Models of amyloid precursor protein processing

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Authors and Affiliations

  1. all in the Department of Neurobiology, H Cheng, P Gong and X Meckler are Postdoctoral Scholars, KS Vetrievel is a Research Associate (Assistant Professor), A Parent is a Research Associate Professor, and G Thinakaran is an Associate Professor, University of Chicago, Chicago, IL, USA.,

    Haipeng Cheng, Kulandaivelu S Vetrivel, Ping Gong, Xavier Meckler, Angèle Parent & Gopal Thinakaran

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  1. Haipeng Cheng
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Correspondence to Gopal Thinakaran.

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Cheng, H., Vetrivel, K., Gong, P. et al. Mechanisms of Disease: new therapeutic strategies for Alzheimer's disease—targeting APP processing in lipid rafts. Nat Rev Neurol 3, 374–382 (2007). https://doi.org/10.1038/ncpneuro0549

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