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While pathogenic genetic mutations have been implicated in \u223c2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of \u03b2-amyloid (A\u03b2), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine A\u03b2 in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1\u0394E9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases A\u03b2 levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into \u03b1-, \u03b2-, and \u03b3-secretase derived metabolites. We propose that LR11 regulates APP processing and A\u03b2 accumulation<jats:italic>in vivo<\/jats:italic>and is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer's disease susceptibility in humans.<\/jats:p>","DOI":"10.1523\/jneurosci.4582-08.2008","type":"journal-article","created":{"date-parts":[[2008,11,26]],"date-time":"2008-11-26T18:29:23Z","timestamp":1227724163000},"page":"12877-12886","source":"Crossref","is-referenced-by-count":119,"title":["Loss of LR11\/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer's Disease"],"prefix":"10.1523","volume":"28","author":[{"given":"Sara E.","family":"Dodson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav M.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinit","family":"Karmali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason 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