Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

The Alcadeins (Alcs)/calsyntenins and the amyloid β-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent γ-cleavage that leads to the secretion of the amyloid β-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid β-protein may contribute to neural disorders. The Alcadeins (Alcs)/calsyntenins and the amyloid β-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent γ-cleavage that leads to the secretion of the amyloid β-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid β-protein may contribute to neural disorders. IntroductionThe deposition and accumulation of amyloid β-protein (Aβ) 1The abbreviation used are: Aβ, amyloid β-protein; AICD, APP cytoplasmic fragment cleaved by γ-secretase; Alc, Alcadein; AlcICD, Alcadein cytoplasmic fragment cleaved by γ-secretase; AlcαΔE, FLAG-tagged AlcICD; APP, amyloid β-protein precursor; AD, Alzheimer's disease; β-Alc, a short peptide generated by secondary cleavage of CTF1; CTF, carboxyl-terminal fragment; CTF1, carboxyl-terminal fragment of Alcs cleaved at primary cleavage site ζ; CTFα, carboxyl-terminal fragment of APP cleaved at α-site; CTFβ, carboxyl-terminal fragment of APP cleaved at β-site; LLnL, N-acetyl-leucyl-norleucinal; DAPT, N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester; HA, haemoagglutinin; PS, presenilin; sAlc, large extracellular amino-terminal domain truncated at the primary site of Alc; sAPP, large extracellular amino-terminal domain of APP truncated at the α- and/or β-sites; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; HEK, human embryonic kidney; IP, immunoprecipitates. in the human brain are hallmarks of Alzheimer's disease (AD) (1Selkoe D.J. Nature. 2003; 426: 900-904Google Scholar). Amyloid β-protein precursor (APP) is the precursor of Aβ. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2Kang J. Lemaire H.G. Unterbeck A. Salbaum J.M. Masters C.L. Grzeschik K.H. Multhaup G. Beyreuther K. Muller-Hill B. Nature. 1987; 325: 733-736Google Scholar). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3Borg J.-P. Yang Y. De Taddeo-Borg M. Margolis B. Turner R.S. J. Biol. Chem. 1998; 273: 14761-14766Google Scholar, 4Russo T. Faraonio R. Minopoli G. De Candia P. De Renzis 1998; Scholar, T. Y. Y. T. J. Biol. Chem. Scholar, J. A. A. J. Scholar, P. J. Biol. Chem. Scholar, K. K. Y. T. J. Biol. Chem. Scholar). of these adaptor proteins is X11L (the X11-like which with the cytoplasmic domain of APP and APP metabolism T. Y. Y. T. J. Biol. Chem. Scholar, Y. A. Y. T. J. Biol. Chem. 2003; Scholar). that to the by which X11L APP found that the which protein are and proteins Y. A. Y. T. J. Biol. Chem. 2003; Scholar). proteins are also as which as functions R. J. P. Scholar, G. A. M. K. J. P. Scholar). The Alcadeins of and and and of which are transmembrane proteins and a in their cytoplasmic to APP Y. A. Y. T. J. Biol. Chem. 2003; does with the cytoplasmic domain of APP. the the is by the domain of in the formation of a tripartite complex in the brain Y. A. Y. T. J. Biol. Chem. 2003; Scholar). The formation of this complex the of APP metabolism and suppresses the of Aβ. its with Alc also tripartite complex with a carboxyl-terminal fragment of APP that from its cleavage at the α- and/or The complex the of the cleavage of the because the of with its with Y. A. Y. T. J. Biol. Chem. 2003; Scholar). it has that APP and Alc in neurons Y. A. Y. T. J. Biol. Chem. 2003; and that is cleaved R. J. P. Scholar). that APP and Alc may metabolized in a by a the found APP, the Alcs are cleaved by the a primary cleavage in their extracellular cleavages to the secretion of an short peptide and the intracellular domain of Alc (AlcICD). AlcICD the gene transactivation of the APP intracellular domain that APP and Alc are coordinately metabolized to the gene transactivation of APP. that these proteins an in neural of the metabolic regulation of APP and Alc and the of the regulation by APP and Alc in the gene transactivation may to neural and disease in Alcadein to and as previously Y. A. Y. T. J. Biol. Chem. 2003; Scholar). The and of and and of the and of The and of to The and B. P. P. K. A. R. Nature. Y. T. J. Biol. Chem. 1998; 273: and T. Y. Y. T. J. Biol. Chem. human of human and human of human by and the the at their the at the generated and which protein of to The used to the which a in which and by The and by the peptide of also to and K. K. Y. T. J. Biol. Chem. at the to a at its has Y. A. Y. T. J. Biol. Chem. 2003; Scholar). The a peptide of the and of human The a peptide of the and of human the cytoplasmic domain of the Alc proteins to which a the Alc the from Alc, and with other Alc proteins from the to which The cytoplasmic has M. T. P. T. and from The amino-terminal fragment and carboxyl-terminal fragment of in of and and at for at The then at for at to the P. De P. J. Biol. Scholar). The in and and at for the in the of an by a and subjected to embryonic as previously Y. A. Y. T. J. Biol. Chem. 2003; with the of various of The and in with and The to and with and and A. De B. Biol. also by the and its fragment and The proteins and the and then subjected to the protein of and in and in in and with the and the the with with with The the in with various of the in and in the of the of in a used of The and the activity of the gene by the of the in and the activity to the to the of in a to APP and for previously reported that Alc and APP a tripartite complex by cytoplasmic with that the proteins in and that tripartite complex formation APP metabolism Y. A. Y. T. J. Biol. Chem. 2003; Scholar). Alcs are as is APP, and a has that the proteins are cleaved R. J. P. Scholar). to that the Alcs are metabolized in a to is that APP is cleaved at α- and in its extracellular and that this releases the large extracellular amino-terminal domain and the intracellular carboxyl-terminal fragments D.J. Scholar). We the Alcs also undergo cleavage at a primary site that a large extracellular amino-terminal domain and a short cytoplasmic carboxyl-terminal fragment and in as APP The by with the The and also from the by with and by with the The for and and the for in the with the Alc the the fragments in the the Alcs are cleaved by a primary cleavage to APP are cleaved at and/or by the complex, which in the secretion of and releases the T. Y. R. K. M. Y. J. Biol. Chem. 2003; Scholar). It is that the APP in the in the of the T. P. A. G. Scholar). that of may to other proteins cleaved by the Alcs proteins are by the the intracellular of increased in the of and and that and are of as is APP and the intracellular of the of in the of and may that is a of the However, the that the of may cleaved by an by the in The of the by that the does the primary cleavage event of the that γ-cleavage of Alcs their primary which is to APP is of AlcICD by in and of in the of with and their at for in the of The of by with the the the of and fragments in the brain in and the of by with the The a of the The may a of The to the of the protein also that Alc is cleaved by a The complex is of at PS, and and is an for activity G. M. A. T. A. Yang P. Y. M. Y. R. A. P. P. Nature. Scholar, R. G. J. M. J. M. M. B. J. M. R. Scholar, T. M. M. Y. G. T. Nature. 2003; Scholar). We the of the from protein by and and A. De B. Biol. The an in intracellular because the of to in these the in the that and a accumulation of intracellular also when the to a the is with B. P. P. K. A. R. Nature. in with and then the of The the show that is cleaved by with and are of and of the by the of Alc that Alc is subjected to a primary cleavage event that and that is then by a secondary It is that the event in the secretion of a short peptide and the of AlcICD the We the primary cleavage site of by the of to The amino-terminal the protein that from the it that the amino-terminal of the is the primary cleavage site of is the peptide and the which is to from an the at and Y. A. Y. T. J. Biol. Chem. 2003; the cleavage site that the and We this cleavage which is in the extracellular domain, We also the amino-terminal of The which is to the that the the peptide and of which that the amino-terminal the of an peptide by the cleavage of structure of the used in this is cleaved and by the and by the primary as and the by the complex as and to the primary cleaved of the and generated The the by the Y. A. Y. T. J. Biol. Chem. 2003; Scholar). transmembrane domain. of FLAG-tagged and proteins in with The of by with the the secretion of from with and for in the of the The and of subjected to and then by with the The the that generated by the cleavage of is generated in and and with The and of subjected to and by with the The of by the of intracellular AlcαΔE, and these then that to the in which a of The are the of and the are that Alc an peptide by the secondary cleavage of by the which the and in and The FLAG-tagged protein then in and the with the the that the carboxyl-terminal of and the and also the that generated from by to the as the and then the peptide it is generated from by with various Yang B. R. J. Biol. Chem. N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl P. B. M. J. J. Yang J. The and subjected to with the which the a and by with the the of in the as a of fragments it from the However, in the of the the which that is generated from by may cleaved at by the of is by in and and the secretion of the The secretion in because the of the to the intracellular of the in secretion suppressed in the and that is generated by cleavage and then the extracellular the of APP is in the intracellular domain fragment of APP is generated by in this because it is subjected to intracellular Y. T. K. Y. J. Biol. Chem. Scholar, G. Y. B. Scholar). We the to the of for at in the of The and then by with the cytoplasmic domain The and fragments generated from the The with the AlcICD that from their probably because these a large Y. A. Y. T. J. Biol. Chem. 2003; Scholar). the of these AlcICD which that generated by the cleavage of the this because it that the of does in when are with is that may of in the of which is to may the for the in the and/or may the of the a may cleaved by the in is to that the of and AlcICD is physiological metabolism of Alc in the brain and the protein and its metabolic by with the cytoplasmic We the and fragments with the The in may an of because these with that the primary and secondary cleavages of that and AlcICD are physiological that in of and APP of the of a with found previously that Alc the of APP metabolism Y. A. Y. T. J. Biol. Chem. 2003; Scholar). the that the Alc proteins are metabolized in a as APP, APP the of Alc metabolism by a tripartite complex of Alc, and APP. it that the of Alc and APP are coordinately by the formation and of the tripartite this with X11L in the of APP, and the secretion of with the in the The of X11L APP suppressed secretion to of the by that with and However, of X11L and APP suppressed secretion to and of APP its secretion and the of intracellular increased and which that X11L the intracellular metabolism of X11L and APP previously Y. A. Y. T. J. Biol. Chem. 2003; the intracellular metabolism of APP is by the of X11L and and The X11L and in the the together show that the primary event that and is by X11L in an as secretion Y. A. Y. T. J. Biol. Chem. 2003; Scholar). the primary metabolic of APP and may of X11L and APP with for the with and in the of the The and by with the The and of by with the and and (APP) The of by the of intracellular and these then that to the in which a of The are the of and the are that and APP, of X11L with by the when APP It also that of X11L with APP by the when Alc Y. A. Y. T. J. Biol. Chem. 2003; and that the metabolism of APP and Alc, at with to the secretion of extracellular domain by cleavage at the is by the formation of a tripartite complex that is by the intracellular of Alc and APP with also previously that Alc the of the γ-cleavage of APP Y. A. Y. T. J. Biol. Chem. 2003; Scholar). APP the of the γ-cleavage of Alc and in with X11L in the of APP The of by X11L and APP this and with The and as a of APP does secretion suppresses and the and CTF1, and this is by the formation of a tripartite complex CTF1, and APP. of X11L and APP the of with and in the of with the to of in The for and the with the The then by with The of by the of intracellular and these then that to the in which a of The are the of and the are of with with and the to of in The for in the of and then The with the and the and of by with the the amino-terminal fragment and and the of amino-terminal fragment of CTF, carboxyl-terminal fragment of of X11L and APP the of with with and in the of with the to of in The for in the of and then The with the and the by with for the amino-terminal of X11L and APP has that the APP to with by a when the are with G. M. J. Biol. Chem. Scholar). Alc is a it is that also with and in in the of by with an and these by with and the of LLnL, the protein and the and carboxyl-terminal fragments of with in the of LLnL, a the amino-terminal fragment of and that the Alc with the of X11L and APP the of with to the of X11L and Alc the of APP with Y. A. Y. T. J. Biol. Chem. 2003; Scholar). and in the of X11L with APP We in the of the a of and which that X11L suppressed the and when APP with it the and that APP the of X11L by a complex of AlcαΔE, and APP. that X11L the of with the of is to X11L suppresses the of from together that APP and Alc are to by a complex via X11L and that their metabolism in the is probably by the of X11L from this and of AlcICD by with is that with and that this intracellular metabolism D.J. J. Biol. Chem. Scholar). AICD, AlcICD a to which is to with and the the of has to which AlcICD from interacting with X11L Y. A. Y. T. J. Biol. Chem. 2003; Scholar). The protein in to the that generated from the with that AICD, AlcICD associate with FE65. We also that with generated by of and APP with the The by with the cytoplasmic the cytoplasmic with APP The also the CTF1, and with that with generated of AlcICD metabolism and of AlcICD of CTF1, and with FE65. with in the of the to of in The with the The and of by with the and with in the of the to of in The with the The and of by with the CTF1, and CTF1, generated generated of by FE65. with with in the of the to of in the of by with The a of the in the subjected to of and cytoplasmic of by with of the of with with The with the and with with The also and of The AlcICD in with in the of and the intracellular of CTF1, and by with the The of that in by of the The increased when the intracellular of in the cytoplasmic the of it is that the metabolism of it has the AlcICD is by its with in the which is also for D.J. J. Biol. Chem. has reported that the by its with A. J. Scholar). the intracellular of AlcICD in the of its a cytoplasmic However, when with in the which that is the because of its with FE65. AlcICD is to with to its metabolism and and FE65-dependent by is to it with Scholar). AlcICD with and the as does AICD, AlcICD also the protein is in with and the gene activity is as reported gene transactivation activity is in the of and in this with FE65-dependent gene transactivation activity and that AlcICD does gene transactivation when with and the gene transactivation by suppressed and the with binding of the gene transactivation and of and FE65-dependent gene transactivation by of the gene transactivation by and FE65. with and with in the of The transactivation are the of the transactivation of the to that of the The the The by of by by of the and FE65. with and in the of the to of in The with the of the of The and of of then by with the that this of AlcICD is that it competes with for a in with in the of and the and subjected to with the The then by with the of the of the a large of with which that these associate However, when with and the a of with a of when a large of the with the of in the of with that the binding of to is in the of because competes with for the with FE65. suppresses the gene transactivation by We also APP in the We found that the protein gene activity in the of that this activity suppressed by generated FE65-dependent gene transactivation, and this suppressed by the generated previously that Alc a complex with APP in the brain the cytoplasmic with which to Alc and APP Y. A. Y. T. J. Biol. Chem. 2003; Scholar). this tripartite complex is APP with to its in the APP is cleaved by the α- and/or in the the also a tripartite complex with X11L and the to by the and the of and from by this the large of because of cleavage by Y. A. Y. T. J. Biol. Chem. 2003; Scholar). Alc is a transmembrane protein that the receptor-like structure as APP. We and found that the APP, cleaved and R. J. P. Scholar). the reported the primary cleavage site of and it in the extracellular that CTF1, the cytoplasmic domain fragment of generated by this primary cleaved by as is APP. here that Alc is a of reported that a of proteins as G. Scholar, K. J. Biol. Chem. Scholar, K. R. J. Biol. Chem. 2003; Scholar, J. Biol. Chem. 2003; Scholar, Y. J. Biol. Chem. 2003; Scholar, Y. T. T. J. Biol. Scholar, P. A. J. A. R. 2003; Scholar, P. J. G. A. P. T. J. Scholar, J. Biol. Chem. Scholar, J. P. De B. G. J. Biol. Chem. 2003; Scholar, T. J. Biol. Chem. 2003; Scholar). it is that are a of and that is for APP and R. 2003; of that Alc is cleaved by is that the cleavages of APP and Alc We found that when Alc tripartite complex with X11L and APP, its primary cleavage is and the of and is the Alc is cleaved at the primary metabolic is to the of APP when AlcαΔE, which the of the primary in short in the are to the amino-terminal of the γ-cleavage of However, when a tripartite complex with X11L and APP, the cleavage of by suppressed because the and cleavage by is by an Y. A. Y. T. J. Biol. Chem. 2003; Scholar). together the that APP and Alc are coordinately metabolized because when proteins a complex their intracellular with their primary and secondary cleavages are However, when the tripartite complex is APP and Alc are subjected to cleaved regulation that the complex formation in the is in as it may in the proteins subjected to cleavage that leads the increased of and It of to is a in the formation of of APP APP X11L and Alcs Alc in and the metabolism of APP and Alc and the regulation of gene transactivation by and APP metabolism and Alc metabolism are suppressed by with each other their in the with the tripartite complex APP and Alc X11L from the complex, APP and Alc are cleaved in a at their primary cleavage and then at their secondary The APP protein and by the of and the Alc protein and AlcICD by the of and with and gene transactivation AlcICD also with and the FE65-dependent gene transactivation activity of by the and in the and/or the FE65-dependent gene transactivation reciprocally by of AlcICD with γ-cleavage of APP the cytoplasmic fragment AICD, which an in gene transactivation it with Scholar). proteins as and are to APP in this gene transactivation Y. T. T. J. Biol. Scholar, R. Nature. 1998; Scholar). AlcICD also to AlcICD to to However, AlcICD show gene transactivation activity in the of FE65. found that AlcICD suppressed the FE65-dependent gene transactivation activity of for this is that AlcICD competes with for to the of the and complex is by that in the of AlcICD, large of AICD, is in the of an for to in the of However, because found that the in the of it that the complex of AlcICD and may and FE65-dependent gene transactivation in the it is that the of AlcICD suppresses gene transactivation that the AlcICD as a that gene the APP and Alc are to subjected to primary extracellular cleavage by extracellular However, the of the primary cleavage APP and cleaved by a tripartite complex their in the with in the of and AlcICD is to by their with a of this the gene transactivation of may by as from the and T. Y. Y. T. J. Biol. Chem. Scholar, K. K. Y. T. J. Biol. Chem. Scholar, Y. A. Y. T. J. Biol. Chem. 2003; the of and the gene transactivation of to by of APP and/or with a of Alc, and the metabolic regulation of APP and Alc and the of gene transactivation by Alc is in in the metabolism of APP and Alc that the of their cleavages the of and AlcICD and may the of by may the that is because of the of the increased of Aβ. gene transactivation by an increased of may suppressed by the and increased of AlcICD to that gene transactivation is by the of AlcICD may of the and that IntroductionThe deposition and accumulation of amyloid β-protein (Aβ) 1The abbreviation used are: Aβ, amyloid β-protein; AICD, APP cytoplasmic fragment cleaved by γ-secretase; Alc, Alcadein; AlcICD, Alcadein cytoplasmic fragment cleaved by γ-secretase; AlcαΔE, FLAG-tagged AlcICD; APP, amyloid β-protein precursor; AD, Alzheimer's disease; β-Alc, a short peptide generated by secondary cleavage of CTF1; CTF, carboxyl-terminal fragment; CTF1, carboxyl-terminal fragment of Alcs cleaved at primary cleavage site ζ; CTFα, carboxyl-terminal fragment of APP cleaved at α-site; CTFβ, carboxyl-terminal fragment of APP cleaved at β-site; LLnL, N-acetyl-leucyl-norleucinal; DAPT, N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester; HA, haemoagglutinin; PS, presenilin; sAlc, large extracellular amino-terminal domain truncated at the primary site of Alc; sAPP, large extracellular amino-terminal domain of APP truncated at the α- and/or β-sites; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; HEK, human embryonic kidney; IP, immunoprecipitates. in the human brain are hallmarks of Alzheimer's disease (AD) (1Selkoe D.J. Nature. 2003; 426: 900-904Google Scholar). Amyloid β-protein precursor (APP) is the precursor of Aβ. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2Kang J. Lemaire H.G. Unterbeck A. Salbaum J.M. Masters C.L. Grzeschik K.H. Multhaup G. Beyreuther K. Muller-Hill B. Nature. 1987; 325: 733-736Google Scholar). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3Borg J.-P. Yang Y. De Taddeo-Borg M. Margolis B. Turner R.S. J. Biol. Chem. 1998; 273: 14761-14766Google Scholar, 4Russo T. Faraonio R. Minopoli G. De Candia P. De Renzis 1998; Scholar, T. Y. Y. T. J. Biol. Chem. Scholar, J. A. A. J. Scholar, P. J. Biol. Chem. Scholar, K. K. Y. T. J. Biol. Chem. Scholar). of these adaptor proteins is X11L (the X11-like which with the cytoplasmic domain of APP and APP metabolism T. Y. Y. T. J. Biol. Chem. Scholar, Y. A. Y. T. J. Biol. Chem. 2003; Scholar). that to the by which X11L APP found that the which protein are and proteins Y. A. Y. T. J. Biol. Chem. 2003; Scholar). proteins are also as which as functions R. J. P. Scholar, G. A. M. K. J. P. Scholar). The Alcadeins of and and and of which are transmembrane proteins and a in their cytoplasmic to APP Y. A. Y. T. J. Biol. Chem. 2003; does with the cytoplasmic domain of APP. the the is by the domain of in the formation of a tripartite complex in the brain Y. A. Y. T. J. Biol. Chem. 2003; Scholar). The formation of this complex the of APP metabolism and suppresses the of Aβ. its with Alc also tripartite complex with a carboxyl-terminal fragment of APP that from its cleavage at the α- and/or The complex the of the cleavage of the because the of with its with Y. A. Y. T. J. Biol. Chem. 2003; Scholar). it has that APP and Alc in neurons Y. A. Y. T. J. Biol. Chem. 2003; and that is cleaved R. J. P. Scholar). that APP and Alc may metabolized in a by a the found APP, the Alcs are cleaved by the a primary cleavage in their extracellular cleavages to the secretion of an short peptide and the intracellular domain of Alc (AlcICD). AlcICD the gene transactivation of the APP intracellular domain that APP and Alc are coordinately metabolized to the gene transactivation of APP. that these proteins an in neural of the metabolic regulation of APP and Alc and the of the regulation by APP and Alc in the gene transactivation may to neural and disease in