Wu, P.-F.P.-F.WuBhore, N.N.BhoreLee, Y.-L.Y.-L.LeeChou, J.-Y.J.-Y.ChouChen, Y.-W.Y.-W.ChenWu, P.-Y.P.-Y.WuWEN-MING HSULee, H.H.LeeHuang, Y.-S.Y.-S.HuangLu, P.-J.P.-J.LuHSIN-YU LEE2021-05-032021-05-0320200892-6638https://www.scopus.com/inward/record.uri?eid=2-s2.0-85088151832&doi=10.1096%2ffj.202000113R&partnerID=40&md5=51107686d51882980f1f1fb436298735https://scholars.lib.ntu.edu.tw/handle/123456789/558741Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aβ production. Given that PI(4,5)P2 is produced by type 1 phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), we sought to determine whether the level of PIP5K type Iα (PIP5K1A) can affect production of Aβ by modulating the lipid composition of the membrane. Using a HEK-derived cell line that constitutively expresses yellow fluorescent protein-tagged APP (APP-YFP), we demonstrated that overexpression of PIP5K1A results in significant enhancement of non-amyloidogenic APP processing and a concomitant suppression of the amyloidogenic pathway, leading to a marked decrease in secreted Aβ. Consistently, cells overexpressing PIP5K1A exhibited a significant redistribution of APP-YFP from endosomal compartments to the cell surface. Our findings suggest that PIP5K1A may play a critical role in governing Aβ production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD. ? 2020 Federation of American Societies for Experimental BiologyenAlzheimer's diseaseamyloid precursor proteinamyloid-βphosphatidylinositol-4-phosphate 5-kinase type 1 α[SDGs]SDG3ADAM10 endopeptidase; alpha secretase; amyloid beta protein; amyloid beta protein[1-40]; amyloid beta protein[1-42]; amyloid precursor protein; anterior pharynx defective 1 protein; beta secretase; beta secretase 1; cell surface protein; gamma secretase; membrane lipid; nicastrin; phosphatidylinositol 4 phosphate 5 kinase type 1alpha; phosphatidylinositol 4 phosphate kinase; presenilin 1; unclassified drug; yellow fluorescent protein; 1-phosphatidylinositol-4-phosphate 5-kinase; amyloid beta protein; phosphatidylinositol 4,5 bisphosphate; phosphotransferase; animal cell; Article; biotinylation; brain cell; cell surface; controlled study; down regulation; embryo; endosome; gene overexpression; HEK293T cell line; human; human cell; internalization; lipid composition; lipid raft; microsome membrane; nonhuman; priority journal; protein degradation; protein homeostasis; protein processing; protein secretion; rat; Alzheimer disease; animal; genetics; HEK293 cell line; metabolism; pathology; Alzheimer Disease; Amyloid beta-Peptides; Animals; HEK293 Cells; Humans; Phosphatidylinositol 4,5-Diphosphate; Phosphotransferases (Alcohol Group Acceptor); Ratsjournal article10.1096/fj.202000113R326868652-s2.0-85088151832