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.

Show MeSH

Related in: MedlinePlus

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.
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fig1: 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.

Mentions: In all developed countries, humans live longer and longer. Although we all wish to enjoy increased longevity, a longer life is unfortunately associated with a dramatic increase for the risk of Alzheimer's disease (AD). This has been widely recognized for years and numerous scientists have studied the cellular mechanisms causing AD with the goal of finally identifying targets for treatment. Indeed, it is likely that all genes directly involved in the generation of the deadly amyloid β-peptide (Aβ), which forms the disease-defining amyloid plaques, have now been identified (Haass, 2004). Currently, it is clear that Aβ is generated by proteolytic processing of β-amyloid precursor protein (APP), and two amyloidogenic secretases, β- and γ-secretase, are involved (Fig. 1). The β-secretase, β-site APP cleaving enzyme (BACE), is a typical aspartyl protease. γ-Secretase, however, is an unusual aspartyl protease complex composed of four individual proteins (presenilin, nicastrin, APH-1, and PEN-2), with presenilin carrying the protease active site (Haass, 2004). γ-Secretase is uncommon not only in its molecular composition but also in its proteolytic activity, since it is able to cleave its substrate within the membrane (Fig. 1). A prerequisite of this intramembrane cut is the release of the ectodomain of APP via cleavage by BACE or α-secretase. Removal of the ectodomain by BACE results in the production of Aβ following γ-secretase cleavage, whereas ectodomain cleavage by α-secretase is nonamyloidogenic since it cuts within the Aβ domain (Fig. 1).


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: 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.
Mentions: In all developed countries, humans live longer and longer. Although we all wish to enjoy increased longevity, a longer life is unfortunately associated with a dramatic increase for the risk of Alzheimer's disease (AD). This has been widely recognized for years and numerous scientists have studied the cellular mechanisms causing AD with the goal of finally identifying targets for treatment. Indeed, it is likely that all genes directly involved in the generation of the deadly amyloid β-peptide (Aβ), which forms the disease-defining amyloid plaques, have now been identified (Haass, 2004). Currently, it is clear that Aβ is generated by proteolytic processing of β-amyloid precursor protein (APP), and two amyloidogenic secretases, β- and γ-secretase, are involved (Fig. 1). The β-secretase, β-site APP cleaving enzyme (BACE), is a typical aspartyl protease. γ-Secretase, however, is an unusual aspartyl protease complex composed of four individual proteins (presenilin, nicastrin, APH-1, and PEN-2), with presenilin carrying the protease active site (Haass, 2004). γ-Secretase is uncommon not only in its molecular composition but also in its proteolytic activity, since it is able to cleave its substrate within the membrane (Fig. 1). A prerequisite of this intramembrane cut is the release of the ectodomain of APP via cleavage by BACE or α-secretase. Removal of the ectodomain by BACE results in the production of Aβ following γ-secretase cleavage, whereas ectodomain cleavage by α-secretase is nonamyloidogenic since it cuts within the Aβ domain (Fig. 1).

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