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Subcellular localization of distinct γ-secretase complexes defines substrate specificity

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Role of gamma-secretase heterogeneity in Alzheimer's disease

An ambitious EU project has looked at the possible roles of distinct gamma-secretase enzyme complexes in a cell. Results have opened up a new interest in intracellular Abeta accumulation in the course of Alzheimer's disease pathogenesis.


Gamma-secretase is a key enzyme in Alzheimer's disease (AD). Among other proteins, it cleaves amyloid precursor protein (APP), liberating the Abeta peptide. Controlling APP proteolytic processing remains a crucial strategy in the development of therapies for this neurodegenerative disease. Already experienced in research on one of the sub-units of gamma secretase, presenilin (PSEN), the GSEC-AD (Subcellular localization of distinct γ-secretase complexes defines substrate specificity) project investigated how distinct PSEN1 and PSEN2 complexes are distributed in the cell and how this affects substrate specificity. The researchers found that the PSEN2-containing γ-secretases are restricted in late endosomes/lysosomes while PSEN1 complexes are more broadly distributed in the cell. This forms not only a basis for targeting different substrates, but the study revealed that particularly PSEN2 complexes contribute to the accumulation of intracellular Abeta peptide more than PSEN1 and that all PSEN2 complex mutations dramatically increase the ratio of toxic Abeta peptides in the cell. Progressive accumulation of intracellular Abeta peptide has been found in AD mice and humans in very early, preclinical stages of the pathogenesis and is suggested to be important in disease onset. Simply cutting γ-secretase activity is not a therapeutic option for AD as the enzyme is involved with crucial metabolic pathways such as Notch in cell signalling. Interfering with these functions leads to serious side effects. However, the outcome of this project suggests that an alternative might be to search for inhibitors that more selectively inhibit PSEN2/γ-secretase thereby targeting the toxic intracellular pool of Aβ only while leaving the processing of other substrates largely untouched. GSEC-AD research results have started us on the path of understanding the intricacies of γ-secretase action in relation to AD. Selective targeting of the enzyme in relation to AD alone will be the answer to a cure for AD. Further details of the research can be found on the researcher lab website.


Alzheimer's disease, gamma secretase, amyloid precursor protein, Abeta peptide, presenilin, GSEC-AD

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