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

Kaether C, Haass C - J. Cell Biol. (2004)

Bottom Line: The cutting procedure is thought to be cholesterol dependent and strategies to lower cholesterol as therapeutic treatment are under intensive investigation.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.

View Article: PubMed Central - PubMed

Affiliation: Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilans University, München, Germany.

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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A model describing the effects of cholesterol reduction on Aβ generation. For details, see text.
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fig2: A model describing the effects of cholesterol reduction on Aβ generation. For details, see text.

Mentions: In this issue, the researchers provide a novel and unexpected explanation for why secretases are localized to cholesterol rich membrane domains. They present data suggesting that the DRM association of BACE restricts its access to APP, which they demonstrate accumulates in detergent sensitive membrane domains outside of DRMs (see Fig. 2). This may indicate aberrant access of APP to DRMs, and hence aberrant Aβ production, during AD or it may indicate that even under physiological conditions some APP molecules come into close contact with DRMs. The latter seems more likely, since Aβ is a physiologically normal product and not produced just in the brains of AD patients (Haass, 2004). These findings also demonstrate a completely novel cellular mechanism for controlling protease activity. Cells undergo major efforts to prevent proteases from contacting proteins not destined to be digested. This is accomplished by numerous mechanisms including synthesis of inactive proforms to be activated at appropriate sites, tagging protease substrates with ubiquitin, sequestering proteases in membrane surrounded environments (endosomes/lysosomes), or hiding the active sites of proteases within narrow tunnels (proteasomes). Abad-Rodriguez et al. (2004) and Vetrivel et al. (2004) add yet another control mechanism. They show that lipids can build an invisible boundary, corralling the γ-secretase complex and BACE away from their substrate, APP. Certainly, this mechanism did not evolve to protect us from AD. So why do the secretases concentrate within DRMs? A probable explanation is that γ-secretase is involved in several signaling pathways including Notch signaling (Selkoe and Kopan, 2003; Haass, 2004) and concentrating the proteolytic machinery in small membrane domains facilitates these processes. This would, however, imply that physiological substrates such as Notch and others must gain access to DRMs, an observation yet to be made.


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

Kaether C, Haass C - J. Cell Biol. (2004)

A model describing the effects of cholesterol reduction on Aβ generation. For details, see text.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172467&req=5

fig2: A model describing the effects of cholesterol reduction on Aβ generation. For details, see text.
Mentions: In this issue, the researchers provide a novel and unexpected explanation for why secretases are localized to cholesterol rich membrane domains. They present data suggesting that the DRM association of BACE restricts its access to APP, which they demonstrate accumulates in detergent sensitive membrane domains outside of DRMs (see Fig. 2). This may indicate aberrant access of APP to DRMs, and hence aberrant Aβ production, during AD or it may indicate that even under physiological conditions some APP molecules come into close contact with DRMs. The latter seems more likely, since Aβ is a physiologically normal product and not produced just in the brains of AD patients (Haass, 2004). These findings also demonstrate a completely novel cellular mechanism for controlling protease activity. Cells undergo major efforts to prevent proteases from contacting proteins not destined to be digested. This is accomplished by numerous mechanisms including synthesis of inactive proforms to be activated at appropriate sites, tagging protease substrates with ubiquitin, sequestering proteases in membrane surrounded environments (endosomes/lysosomes), or hiding the active sites of proteases within narrow tunnels (proteasomes). Abad-Rodriguez et al. (2004) and Vetrivel et al. (2004) add yet another control mechanism. They show that lipids can build an invisible boundary, corralling the γ-secretase complex and BACE away from their substrate, APP. Certainly, this mechanism did not evolve to protect us from AD. So why do the secretases concentrate within DRMs? A probable explanation is that γ-secretase is involved in several signaling pathways including Notch signaling (Selkoe and Kopan, 2003; Haass, 2004) and concentrating the proteolytic machinery in small membrane domains facilitates these processes. This would, however, imply that physiological substrates such as Notch and others must gain access to DRMs, an observation yet to be made.

Bottom Line: The cutting procedure is thought to be cholesterol dependent and strategies to lower cholesterol as therapeutic treatment are under intensive investigation.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.

View Article: PubMed Central - PubMed

Affiliation: Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilans University, München, Germany.

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.

Show MeSH
Related in: MedlinePlus