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P4‐321: Novel regulation of BACE1 by retinoid signaling
Author(s) -
Liao FrancescaFang,
Wang Ruishan,
Diao Shiyong,
Kwak Youngdon,
Bhat Narayan
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.09.066
Subject(s) - pathogenesis , biology , endocrinology , transcription factor , medicine , downregulation and upregulation , retinoid x receptor , retinoid , neuroinflammation , oxidative stress , microbiology and biotechnology , inflammation , biochemistry , immunology , gene , retinoic acid , nuclear receptor
ization and trafficking of APP. Therefore understanding how APP is moved around and controlled is central to developing therapies for AD treatment. Various members of the LDLR family (LRP1, SorLA) have been found to interact with APP and to regulate its trafficking and processing. We recently characterizeda newmemberof theLDLRfamily calledLRP10which shuttles between the trans-Golgi Network (TGN) and endosomes. LRP10 homology to the sorting receptor SorLA leads us to hypothesize that LRP10 is a functional APP receptor involved in APP trafficking and processing Methods: Studies were performed mainly in human neuroblastoma cells (SH-SY5Y) stably expressing LRP10wild-type or trafficking mutant. Protein interactions were determined by immunoprecipitation and pull-down assays. The subcellular localizations were characterized by confocal microscopy. APP processing products were determined by WB and ELISA. Results: LRP10 interacts directly with APP and colocalizes with APP at the TGN. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant targeting of LRP10 (named LRP10-DXXAA) to the endosomal compartment and the plasma membrane and induces the redistribution of APP to early endosomes. Increased expression of LRP10 wild-type reduces processing of APP into Aß and sAPP, while expression of LRP10-DXXAA trafficking mutant increased ß-site cleavage of APP and accelerate generation of Aß. A possible role for LRP10 as risk factor for ADwas supported by preliminary studies indicating decreased levels of LRP10 in post mortem brain tissue of AD patients.Conclusions:Our data show that LRP10 binds to APP andmodulates its intracellular distribution as well as its processing, strengthening the potential role of LRP10 as a novel APP sorting receptor. LRP10 wild-type seems to protect APP from processing into Aß and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced LRP10 receptor expression in the human brain may increase Aß production and plaque formation and promote spontaneous AD.