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Since the first prediction of a genetic link between <jats:italic>PSEN1<\/jats:italic> and <jats:italic>PSEN2<\/jats:italic> with Alzheimer's disease, many research groups from both academia and pharmaceutical industry have sought to unravel how pathogenic mutations in <jats:italic>PSEN<\/jats:italic> cause presenile dementia. <jats:italic>PSEN<\/jats:italic> genes encode polytopic membrane proteins termed presenilins (PS1 and PS2), which function as the catalytic subunit of \u03b3-secretase, an intramembrane protease that has a wide spectrum of type I membrane protein substrates. Sequential cleavage of amyloid precursor protein by BACE and \u03b3-secretase releases highly fibrillogenic \u03b2-amyloid peptides, which accumulate in the brains of aged individuals and patients with Alzheimer's disease. Familial Alzheimer's disease-associated presenilin variants are thought to exert their pathogenic function by selectively elevating the levels of highly amyloidogenic A\u03b242 peptides. In addition to Alzheimer's disease, several recent studies have linked <jats:italic>PSEN1<\/jats:italic> to familiar frontotemporal dementia. Here, we review the biology of PS1, its role in \u03b3-secretase activity, and discuss recent developments in the cell biology of PS1 with respect to Alzheimer's disease pathogenesis.<\/jats:p>","DOI":"10.1186\/1750-1326-1-4","type":"journal-article","created":{"date-parts":[[2006,6,13]],"date-time":"2006-06-13T07:12:08Z","timestamp":1150182728000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["Pathological and physiological functions of presenilins"],"prefix":"10.1186","volume":"1","author":[{"given":"Kulandaivelu S","family":"Vetrivel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-wu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopal","family":"Thinakaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2006,6,12]]},"reference":[{"key":"4_CR1","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.7638622","volume":"269","author":"E Levy-Lahad","year":"1995","unstructured":"Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE: Candidate gene for the chromosome 1 familial Alzheimer's disease locus. 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