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Review
. 2004 Dec 6;167(5):809-12.
doi: 10.1083/jcb.200410090.

A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation

Christoph Kaether  1 , Christian Haass
Affiliations
Review

A lipid boundary separates APP and secretases and limits amyloid beta-peptide generation

Christoph Kaether et al. J Cell Biol. .

Abstract

Millions of patients suffer from Alzheimer's disease, and intensive efforts to find a cure for this devastating disorder center on the proteases, which release the deadly amyloid beta-peptide from its precursor. The cutting procedure is thought to be cholesterol dependent and strategies to lower cholesterol as therapeutic treatment are under intensive investigation. Recent findings suggest that the complete proteolytic machinery required for amyloid beta-peptide generation is located within lipid rafts. Data by Dotti and colleagues (Abad-Rodriguez et al., 2004), in this issue, suggest that rafts isolate the cutting machinery away from its deadly substrate. These findings describe a novel mechanism for controlling proteolytic activity by building a lipid boundary between proteases and their substrates.

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Figures

Figure 1.
Figure 1.
Processing of APP by secretases. α-Secretase cleavage occurs within the Aβ domain and prevents amyloidogenesis. However, a small peptide (p3) is generated by the subsequent cleavage of the C83 fragment by γ-secretase. Besides p3, the large ectodomain (APPs-α) is secreted. A shorter APPs species is secreted upon cleavage by BACE (APPs-β). The resulting C99 fragment is cleaved by γ-secretase to produce Aβ. The γ-secretase cut releases the APP intracellular domain (AICD), which may be involved in nuclear signaling.
Figure 2.
Figure 2.
A model describing the effects of cholesterol reduction on Aβ generation. For details, see text.
See this image and copyright information in PMC

Comment on

References

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