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Correspondence to Christian Haass: chaass{at}med.uni-muenchen.de
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 ß-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 ß-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.
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 ß-peptide (Aß), which forms the disease-defining amyloid plaques, have now been identified (Haass, 2004). Currently, it is clear that Aß is generated by proteolytic processing of ß-amyloid precursor protein (APP), and two amyloidogenic secretases, ß- and -secretase, are involved (Fig. 1). The ß-secretase, ß-site APP cleaving enzyme (BACE), is a typical aspartyl protease.
-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).
-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
-secretase. Removal of the ectodomain by BACE results in the production of Aß following
-secretase cleavage, whereas ectodomain cleavage by
-secretase is nonamyloidogenic since it cuts within the Aß domain (Fig. 1).
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The strong cholesterol dependency of Aß generation suggested that secretases might be located within DRMs and this may regulate the processing of APP. Indeed, Ehehalt et al. (2003) demonstrated that antibody cross-linking induced BACE and APP to copatch within cholesterol-rich microdomains, and this resulted in increased Aß production. This proposed localization of secretases is supported by the recent findings of two different laboratories. Here, Abad-Rodriguez et al. (2004) report that they were able to identify endogenous BACE within DRMs of primary hippocampal neurons. Elsewhere, Vetrivel et al. (2004) recently demonstrated that the completely assembled, biologically active -secretase complexconsisting of the presenilin fragments APH-1, mature Nicastrin, and PEN-2resides within DRMs. Moreover,
-secretase was found in syntaxin 6, syntaxin 13, and VAMP4-positive vesicles, demonstrating that
-secretase accumulates in the DRMs of late Golgi and endosomes (Vetrivel et al., 2004), exactly where BACE is thought to be biologically active (Haass et al., 1995; Vassar et al., 1999; Walter et al., 2001). Similarly, monomeric and oligomeric Aß were concentrated in DRMs in the brains of a mouse model for AD (Lee et al., 1998; Kawarabayashi et al., 2004). Thus, it appears that the complete Aß generating proteolytic machinery coexists within DRMs of the same vesicles.
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 Aß 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 Aß 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 -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
-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.
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Submitted: 15 October 2004
Accepted: 12 November 2004
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