RNA Interference-mediated Silencing of X11α and X11β Attenuates Amyloid β-Protein Levels via Differential Effects on β-Amyloid Precursor Protein Processing

Processing of the β-amyloid precursor protein (APP) plays a key role in Alzheimer disease neuropathogenesis. APP is cleaved by β- and α-secretase to produce APP-C99 and APP-C83, which are further cleaved by γ-secretase to produce amyloid β-protein (Aβ) and p3, respectively. APP adaptor proteins with phosphotyrosine-binding domains, including X11α (MINT1, encoded by gene APBA1) and X11β (MINT2, encoded by gene APBA2), can bind to the conserved YENPTY motif in the APP C terminus. Overexpression of X11α and X11β alters APP processing and Aβ production. Here, for the first time, we have described the effects of RNA interference (RNAi) silencing of X11α and X11β expression on APP processing and Aβ production. RNAi silencing of APBA1 in H4 human neuroglioma cells stably transfected to express either full-length APP or APP-C99 increased APP C-terminal fragment levels and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. RNAi silencing of APBA2 also lowered Aβ levels, but apparently not via attenuation of γ-secretase cleavage of APP. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor protein X11α is particularly attractive with regard to therapeutic potential given that side effects of γ-secretase inhibition due to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided. Processing of the β-amyloid precursor protein (APP) plays a key role in Alzheimer disease neuropathogenesis. APP is cleaved by β- and α-secretase to produce APP-C99 and APP-C83, which are further cleaved by γ-secretase to produce amyloid β-protein (Aβ) and p3, respectively. APP adaptor proteins with phosphotyrosine-binding domains, including X11α (MINT1, encoded by gene APBA1) and X11β (MINT2, encoded by gene APBA2), can bind to the conserved YENPTY motif in the APP C terminus. Overexpression of X11α and X11β alters APP processing and Aβ production. Here, for the first time, we have described the effects of RNA interference (RNAi) silencing of X11α and X11β expression on APP processing and Aβ production. RNAi silencing of APBA1 in H4 human neuroglioma cells stably transfected to express either full-length APP or APP-C99 increased APP C-terminal fragment levels and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. RNAi silencing of APBA2 also lowered Aβ levels, but apparently not via attenuation of γ-secretase cleavage of APP. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor protein X11α is particularly attractive with regard to therapeutic potential given that side effects of γ-secretase inhibition due to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided. The study of amyloidogenic β-amyloid precursor protein (APP) 1The abbreviations used are: APP, β-amyloid precursor protein; Aβ, amyloid β-protein; APPsα, secreted α-secretase cleavage product of APP; APPs, secreted N-terminal ectodomain of APP; RNAi, RNA interference; APP-FL, full-length APP; DAPT, N-(N-(3,5-difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester; siRNA, small interfering RNA; APP-CTF, APP C-terminal fragment. processing at the gene, protein, and cellular levels has been a major focus of Alzheimer disease neuropathogenesis research since the isolation of the APP gene in 1987 (see reviews in Refs. 1Tanzi R.E. Bertram L. Neuron. 2001; 32: 181-184Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar, 2Selkoe D.J. Physiol. Rev. 2001; 81: 741-766Crossref PubMed Scopus (5191) Google Scholar, 3Sisodia S.S. St. George-Hyslop P.H. Nat. Rev. Neurosci. 2002; 3: 281-290Crossref PubMed Scopus (487) Google Scholar). Genetic, neuropathological, and biochemical findings indicate that excessive production and/or accumulation of the amyloid β-peptide (Aβ) plays a fundamental role in the pathogenesis of Alzheimer disease (see reviews in Refs. 1Tanzi R.E. Bertram L. Neuron. 2001; 32: 181-184Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar, 2Selkoe D.J. Physiol. Rev. 2001; 81: 741-766Crossref PubMed Scopus (5191) Google Scholar, 3Sisodia S.S. St. George-Hyslop P.H. Nat. Rev. Neurosci. 2002; 3: 281-290Crossref PubMed Scopus (487) Google Scholar). Aβ is produced from APP through proteolytic processing by two proteases, β- and γ-secretase. Specifically, APP is first hydrolyzed in the extracellular domain, either between Met671 and Asp672 or between residues 682 and 683, by the aspartyl protease β-site APP-cleaving enzyme or β-secretase, a type I transmembrane glycosylated aspartyl protease found in post-Golgi membranes and at the cell surface (4Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3327) Google Scholar, 5Hussain I. Powell D. Howlett D.R. Tew D.G. Meek T.D. Chapman C. Gloger I.S. Murphy K.E. Southan C.D. Ryan D.M. Smith T.S. Simmons D.L. Walsh F.S. Dingwall C. Christie G. Mol. Cell. Neurosci. 1999; 14: 419-427Crossref PubMed Scopus (1002) Google Scholar, 6Sinha S. Lieberburg I. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11049-11053Crossref PubMed Scopus (426) Google Scholar, 7Yan R. Bienkowski M.J. Shuck M.E. Miao H. Tory M.C. Pauley A.M. Brashier J.R. Stratman N.C. Mathews W.R. Buhl A.E. Carter D.B. Tomasselli A.G. Parodi L.A. Heinrikson R.L. Gurney M.E. Nature. 1999; 402: 533-537Crossref PubMed Scopus (1340) Google Scholar). This cleavage by β-secretase generates a 99-residue membrane-associated C-terminal fragment (APP-C99). APP-C99 is further cleaved to release 4-kDa Aβ and the β-APP intracellular domain. This cleavage is achieved by an unusual form of proteolysis in which the protein is cleaved within the transmembrane domain (at residue +40 or +42) by γ-secretase (8Gu Y. Misonou H. Sato T. Dohmae N. Takio K. Ihara Y. J. Biol. Chem. 2001; 276: 35235-35238Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 9Sastre M. Steiner H. Fuchs K. Capell A. Multhaup G. Condron M.M. Teplow D.B. Haass C. EMBO Rep. 2001; 2: 835-841Crossref PubMed Scopus (431) Google Scholar, 10Yu C. Kim S.H. Ikeuchi T. Xu H. Gasparini L. Wang R. Sisodia S.S. J. Biol. Chem. 2001; 276: 43756-43760Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). APP, a single-pass and integral transmembrane protein, is more routinely cleaved by α-secretase, at the site close to the transmembrane domain and in the middle of the Aβ region of APP, to release a large ectodomain (APPsα), leaving a C-terminal fragment of 83 amino acids (APP-C83) in the membrane. Whereas proteolysis of APP-C99 by γ-secretase produces Aβ, proteolysis of APP-C83 by γ-secretase produces p3, a peptide resembling an N-terminally truncated form of Aβ (Refs. 11Esch F.S. Keim P.S. Beattie E.C. Blacher R.W. Culwell A.R. Oltersdorf T. McClure D. Ward P.J. Science. 1990; 248: 1122-1124Crossref PubMed Scopus (1208) Google Scholar and 12Sisodia S.S. Koo E.H. Beyreuther K. Unterbeck A. Price D.L. Science. 1990; 248: 492-495Crossref PubMed Scopus (745) Google Scholar; see review in Ref. 13Wolfe M.S. Curr. Top. Dev. Biol. 2003; 54: 233-261Crossref PubMed Google Scholar). Presenilin and γ-secretase co-fractionate as a detergent-sensitive high molecular mass complex (14Li Y.M. Lai M.T. Xu M. Huang Q. DiMuzio-Mower J. Sardana M.K. Shi X.P. Yin K.C. Shafer J.A. Gardell S.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6138-6143Crossref PubMed Scopus (501) Google Scholar) that includes at least three other proteins, nicastrin/APH-2, APH-1, and PEN-2, all of which are necessary for γ-secretase activity (Refs. 15Francis R. McGrath G. Zhang J. Ruddy D.A. Sym M. Apfeld J. Nicoll M. Maxwell M. Hai B. Ellis M.C. Parks A.L. Xu W. Li J. Gurney M. Myers R.L. Himes C.S. Hiebsch R. Ruble C. Nye J.S. Curtis D. Dev. Cell. 2002; 3: 85-97Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 16Steiner H. Winkler E. Edbauer D. Prokop S. Basset G. Yamasaki A. Kostka M. Haass C. J. Biol. Chem. 2002; 277: 39062-39065Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 17Yu G. Nishimura M. Arawaka S. Levitan D. Zhang L. Tandon A. Song Y.Q. Rogaeva E. Chen F. Kawarai T. Supala A. Levesque L. Yu H. Yang D.S. Holmes E. Milman P. Liang Y. Zhang D.M. Xu D.H. Sato C. Rogaev E. Smith M. Janus C. Zhang Y. Aebersold R. Farrer L.S. Sorbi S. Bruni A. Fraser P. St. George-Hyslop P. Nature. 2000; 407: 48-54Crossref PubMed Scopus (827) Google Scholar; see review in Ref. 18De Strooper B. Neuron. 2003; 38: 9-12Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar). γ-Secretase cleavage of the cytoplasmic tail of APP generates the APP intracellular domain, which contains an absolutely conserved YENPTY motif present in the cytodomains of several and in the residue of motif is and the YENPTY motif as a site for the phosphotyrosine-binding domain present in several adaptor proteins, including the X11α and X11β encoded by APBA1 and bind to the YENPTY motif of APP (Refs. J. E. B. Mol. Cell. Biol. PubMed Scopus Google Scholar and D.M. PubMed Scopus Google Scholar; see review in Ref. R. PubMed Scopus Google Scholar). Overexpression of X11α and X11β has been to APP Yang Y. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and M. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that of X11α can the APP and the levels of the secreted N-terminal ectodomain of APP and Aβ in X11β also cellular APP and the levels of and Aβ D.M. J. K. J. Neurosci. 1999; PubMed Scopus Google Scholar, T. J. Neurosci. 2002; PubMed Google Scholar). X11α and X11β can with via D.M. C. Mol. Cell. Neurosci. 2000; PubMed Scopus Google Scholar). have that of X11α can APP and Aβ production J.R. 2003; PubMed Scopus Google Scholar). K. J. PubMed Scopus Google Scholar) that X11α with γ-secretase not cleavage of APP and Aβ production. the effects of expression of APBA1 and APBA2 or X11α and X11β on APP processing and Aβ production have not been we RNA interference (RNAi) for APBA1 and APBA2 in H4 cells either full-length APP or APP-C99 and the effects of silencing of APBA1 and APBA2 on APP processing and Aβ production. used H4 human neuroglioma cells and H4 cells stably transfected to express either or APP-C99 is the product of β-secretase and contains and not This cell a to effects on APP processing are on APP processing and of APP cell lines in high and transfected H4 cells with RNAi and interfering RNA human the gene X11α and the gene X11β from Wang H. Li H. Kim S. G. Kim Yu G. Xu H. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) used as the transfected cells by of and of and we used the in the for cell The transfected cells in a of cell The cells The γ-secretase in the as a and on and protease and The at for and for proteins the protein of APP as described by R. D.M. G. D. R. PubMed Scopus Google Scholar). of protein from to the proteins to a a proteins in for with a by a with for between used to X11α and used to X11β used to APP-C83 and APP-C99 in The of the the as used the levels of to the levels of APP-FL, and the APP C-terminal fragment the of the X11α to the to for in protein present the in the protein levels of APP-FL, and APP-C83 in the cells with APBA1 or APBA2 as a of in the cells with of Aβ with and with or APBA2), the and secreted Aβ by a as described by R. D.M. G. D. R. PubMed Scopus Google Scholar). with to or with the at with of the cell and The with and at Aβ levels in by with the from with of and of with to the from the APBA1 RNAi and Aβ in H4 first which APBA1 X11α protein levels in H4 cells The cells with either or APBA1 and to in which used to the protein levels of in X11α a in the protein levels of X11α APBA1 with in the of in or APBA1 all the in APBA1 X11α protein levels by to with that RNAi for APBA1 the protein levels of the effects of silencing of APBA1 on APP processing in cells by the protein levels of APP-FL, and APP-C83 APBA1 of APBA1 or siRNA, the cells and to in which used to APP-FL, and The protein levels of APP-C99 and APP-C83 increased in the cells with APBA1 with with a the γ-secretase to the accumulation of APP-C99 and APP-C83 with the to APP-C99 and APP-C83, of APP-C99 and APP-C83 as in the protein levels of in APBA1 or also the protein levels of APP-FL, and APP-C83 in H4 cells and found that in in the of in APBA1 or cells and H4 of APP-FL, and APP-C83 to that APBA1 to a in the of APP-C99 to and a in the of APP-C83 to with as a the γ-secretase to and in the of APP-C99 and APP-C83 to APP-FL, respectively. Aβ levels in the with siRNA, APBA1 siRNA, or to be in we present the in production from in both APBA1 and Aβ levels to a with and that RNAi silencing of APBA1 APP processing and Aβ production in a to that of APBA2 RNAi Aβ but APP Processing in the other protein, X11β by gene APBA2), can APP processing and Aβ production in we APBA2 RNAi in of cells with APBA2 or siRNA, the cells and to in which used to the protein levels of in X11β a in the protein levels of X11β in the cells with APBA2 with with of the to that APBA2 the protein levels of X11β by with the effects of silencing of APBA2 on APP processing in with either APBA2 or siRNA, the cells and to in with in the protein levels of in APBA2 or APBA2 not the protein levels of APP-C99 or APP-C83, used as a in the increased the protein levels of both APP-C99 and APP-C83 with also the protein levels of APP-FL, and APP-C83 in H4 cells and found that in of the protein levels of APP-FL, and APP-C83 in the that to and in the of APP-C99 and APP-C83 to APP-FL, with APBA2 not the of APP-C99 and APP-C83 to with Aβ levels in the with siRNA, APBA2 siRNA, or in both APBA2 and Aβ production with and findings in to APBA1 APBA2 not APP APBA2 also Aβ production in β-secretase to produce and γ-secretase APP-C99 to produce the in APP processing and Aβ production with APBA1 and APBA2 be due to in either β-secretase and/or γ-secretase the we to the in APP processing and Aβ production with APBA1 or APBA2 of APP processing and on APP H4 cells APP-C99 APBA1 RNAi and Aβ in increased β-secretase cleavage of as a for increased we APP-C99 is the product of β-secretase and and not of cells with APBA1 or siRNA, the cells and to in which used to in X11α a in the protein levels of X11α by gene APBA1) in the cells with APBA1 with with in the of in or APBA1 of X11α in the to that APBA1 the protein levels of X11α by the effects of silencing of APBA1 on processing of with APBA1 or siRNA, the cells and to with APBA1 not the protein levels of with in the protein levels of both APP-C99 and APP-C83 in the cells with APBA1 with with also the protein levels of APP-C99 and APP-C83 in H4 cells and found that in in the of in or APBA1 cells and H4 of APP-FL, and APP-C83 that APBA1 to a in the of APP-C99 to and a in the of APP-C83 to with Aβ levels in the from cells with either or APBA1 in APBA1 Aβ production with findings that APBA1 RNAi γ-secretase not cleavage of APP. APBA2 RNAi APP Processing or Aβ in we the effects of APBA2 RNAi on APP processing and Aβ production in with APBA2 or siRNA, the cells and to in which used to the protein levels of X11β a in the protein levels of X11β by gene in the cells with APBA2 with with in the of in or APBA2 of X11β to that APBA2 the protein levels of X11β by with with in the protein levels of APP-FL, and APP-C83 in the cells with APBA2 with with also the protein levels of APP-C99 and APP-C83 in H4 cells and found that in in the of in or APBA2 cells and H4 of APP-FL, and APP-C83 that APBA2 not the of APP-C99 and APP-C83 to Aβ levels in the from cells with or APBA2 in APBA2 not Aβ production with in to APBA1 RNAi, APBA2 RNAi not APP processing or Aβ production in or APP Processing or Aβ in and a we also the effects of or on APP processing and Aβ levels in and found that or not APP processing or Aβ levels with in and cells not that the effects of APBA1 or APBA2 RNAi on APP processing and Aβ levels in not due to or but to the in the protein levels of X11α and Aβ, the key in is from APP via cleavage by two proteases, β- and γ-secretase (4Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3327) Google Scholar, 5Hussain I. Powell D. Howlett D.R. Tew D.G. Meek T.D. Chapman C. Gloger I.S. Murphy K.E. Southan C.D. Ryan D.M. Smith T.S. Simmons D.L. Walsh F.S. Dingwall C. Christie G. Mol. Cell. Neurosci. 1999; 14: 419-427Crossref PubMed Scopus (1002) Google Scholar, 6Sinha S. Lieberburg I. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11049-11053Crossref PubMed Scopus (426) Google Scholar, 7Yan R. Bienkowski M.J. Shuck M.E. Miao H. Tory M.C. Pauley A.M. Brashier J.R. Stratman N.C. Mathews W.R. Buhl A.E. Carter D.B. Tomasselli A.G. Parodi L.A. Heinrikson R.L. Gurney M.E. Nature. 1999; 402: 533-537Crossref PubMed Scopus (1340) Google Scholar). by β-secretase first generates which is further cleaved by γ-secretase to release Aβ and the APP intracellular domain (8Gu Y. Misonou H. Sato T. Dohmae N. Takio K. Ihara Y. J. Biol. Chem. 2001; 276: 35235-35238Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 9Sastre M. Steiner H. Fuchs K. Capell A. Multhaup G. Condron M.M. Teplow D.B. Haass C. EMBO Rep. 2001; 2: 835-841Crossref PubMed Scopus (431) Google Scholar, 10Yu C. Kim S.H. Ikeuchi T. Xu H. Gasparini L. Wang R. Sisodia S.S. J. Biol. Chem. 2001; 276: 43756-43760Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). APP is also cleaved by α-secretase to release a large ectodomain and APP-C83, and APP-C83 is cleaved by γ-secretase to produce and the APP intracellular domain (Refs. 11Esch F.S. Keim P.S. Beattie E.C. Blacher R.W. Culwell A.R. Oltersdorf T. McClure D. Ward P.J. Science. 1990; 248: 1122-1124Crossref PubMed Scopus (1208) Google Scholar and 12Sisodia S.S. Koo E.H. Beyreuther K. Unterbeck A. Price D.L. Science. 1990; 248: 492-495Crossref PubMed Scopus (745) Google Scholar; see review in Ref. 13Wolfe M.S. Curr. Top. Dev. Biol. 2003; 54: 233-261Crossref PubMed Google Scholar). APP adaptor proteins (see review in Ref. R. PubMed Scopus Google including X11α and have been to APP processing and Aβ production Yang Y. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. J. K. J. Neurosci. 1999; PubMed Scopus Google Scholar, T. J. Neurosci. 2002; PubMed Google Scholar, J.R. 2003; PubMed Scopus Google Scholar, K. J. PubMed Scopus Google Scholar, M.S. S.J. L. D.M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Specifically, of X11α and X11β has been to APP levels, to the APP to APPs, and to Aβ levels Yang Y. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. J. K. J. Neurosci. 1999; PubMed Scopus Google Scholar, T. J. Neurosci. 2002; PubMed Google Scholar, J.R. 2003; PubMed Scopus Google Scholar, K. J. PubMed Scopus Google Scholar, M.S. S.J. L. D.M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the effects of of X11α and X11β on APP processing and Aβ production have not been have for the first time, that RNAi silencing of APBA1 and APBA2 X11α and APP processing and Aβ RNAi silencing of APBA1 to increased levels of APP-C99 and APP-C83 in and RNAi for APBA1 Aβ levels the in APP-C99 and APP-C83 levels APBA1 be due either to in the of β-secretase and/or α-secretase or to in γ-secretase cleavage of APP-C99 and between two we have in H4 cells APP-C99 β-secretase cleavage product of APBA1 increased the protein levels of APP-C99 and APP-C83 and the levels of Aβ in the indicate that the in APP processing and Aβ levels APBA1 RNAi are of cleavage of APP and are due to inhibition of cleavage of APP. the effects of APBA1 RNAi on cleavage of APP processing and Aβ production be by RNAi silencing of X11β by APBA2 RNAi Aβ levels but not the protein levels of APP-C99 and or APP-C83 and in APBA2 RNAi of cells not the protein levels of APP-C99 and or APP-C83 and or Aβ levels findings the with the in Aβ levels RNAi silencing of APBA2 not in γ-secretase but in β-secretase cleavage of APP. is also that APBA2 RNAi Aβ levels through other as Aβ be necessary to between findings for the first time, that RNAi of X11α cleavage of APP, to increased accumulation of APP-C99 and APP-C83 and Aβ Overexpression of X11α has also been to APP Yang Y. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. J. K. J. Neurosci. 1999; PubMed Scopus Google Scholar, T. J. Neurosci. 2002; PubMed Google Scholar, J.R. 2003; PubMed Scopus Google Scholar, K. J. PubMed Scopus Google Scholar, M.S. S.J. L. D.M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google including in APP-C99 levels and in Aβ levels K. J. PubMed Scopus Google Scholar). is in silencing of X11α to and not effects on APP processing and Aβ levels with the X11α The phosphotyrosine-binding domain of X11α J. E. B. Mol. Cell. Biol. PubMed Scopus Google Scholar; see review in Ref. R. PubMed Scopus Google Scholar) has been to bind the YENPTY in the the domain of X11α D.M. C. Mol. Cell. Neurosci. 2000; PubMed Scopus Google Scholar) has been to bind to Y.M. Lai M.T. Xu M. Huang Q. DiMuzio-Mower J. Sardana M.K. Shi X.P. Yin K.C. Shafer J.A. Gardell S.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 6138-6143Crossref PubMed Scopus (501) Google Scholar; see review in Ref. R. PubMed Scopus Google Scholar). on might that of X11α on of APP by the YENPTY motif and Aβ levels by of APP the and on the other γ-secretase cleavage of APP by with the γ-secretase of X11α the to be increased accumulation of and levels of Aβ, with APP processing Yang Y. M. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. J. K. J. Neurosci. 1999; PubMed Scopus Google Scholar, T. J. Neurosci. 2002; PubMed Google Scholar, J.R. 2003; PubMed Scopus Google Scholar, K. J. PubMed Scopus Google Scholar, M.S. S.J. L. D.M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). This that the potential effects of X11α on APP on with be necessary to of X11α expression might be to APP processing on with APP processing by for to the YENPTY motif for of APP. APBA1 RNAi silencing the to be to that of the X11α increased accumulation of and Aβ levels due to APP the X11α and that X11α levels be high to APP processing and Aβ production. RNAi silencing of X11β to a in Aβ levels in but not in APBA2 RNAi not APP processing in either cell that APP processing not is that the in Aβ levels APBA2 in either APP processing or Aβ be necessary to X11α and X11β can also with proteins other APP, including a protein for T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google and which are proteins that as for the T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). X11α and X11β bind the cytoplasmic tail of via T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). X11α not with to form a transmembrane proteins in cells M. S.J. B. J. Neurosci. 1999; PubMed Google Scholar, C. T. S. Kim Mol. Biol. Cell. 1999; PubMed Scopus Google Scholar). The domain of X11α has also been to with several other proteins, including D.M. C. Mol. Cell. Neurosci. 2000; PubMed Scopus Google a A. I. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google N. Y. K. M. M. I. A. M. K. H. Y. PubMed Scopus Google the of D.M. S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google and the M. T. D.H. N. Science. 2000; PubMed Scopus Google Scholar). of proteins can X11α have a in the and complex (see review in Ref. R. PubMed Scopus Google Scholar). be in to the effects of RNAi for on the of other silencing of the APP adaptor protein X11α cleavage of APP, to Aβ RNAi silencing of X11β also Aβ levels, but effects on APP with of that of and other APP adaptor proteins might as a therapeutic to and Alzheimer The notion of attenuating γ-secretase cleavage of APP via APP adaptor proteins as X11α is particularly attractive given that potential effects of γ-secretase inhibition due to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided. be necessary to further findings and to the of a therapeutic at Aβ Aβ for of for the of Aβ