title: FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction.
abstract: To investigate the consequences of mutant presenilin-1 (PS-1) expression under the control of the normal PS-1 gene, a gene-targeted mouse bearing the FAD mutation P264L was made. Gene-targeted models are distinct from transgenic models because the mutant gene is expressed at normal levels, in the absence of the wild-type protein. PS-1(P264L/P264L) mice had normal expression of PS-1 mRNA, but levels of the N- and C-terminal protein fragments of PS-1 were reduced while levels of the holoprotein were increased. When crossed into Tg(HuAPP695.K670N/M671L)2576 mice, the PS-1(P264L) mutation accelerated the onset of amyloid (Abeta) deposition in a gene-dosage dependent manner. Tg2576/PS-1(P264L/P264L) mice also had Abeta deposition that was widely distributed throughout the brain and spinal cord. APP(NLh/NLh)/PS-1(P264L/P264L) double gene-targeted mice had elevated levels of Abeta42, sufficient to cause Abeta deposition beginning at 6 months of age. Abeta deposition increased linearly over time in APP(NLh/NLh)/PS-1(P264L/P264L) mice, whereas the increase in Tg2576 mice was exponential. The APP(NLh/NLh)/PS-1(P264L/P264L) double gene-targeted mouse represents an animal model that exhibits Abeta deposition without overexpression of APP.
authors.affiliation: Department of Neurobiology, Cephalon, Inc., West Chester, PA 19380, USA. dflood@cephalon.com
authors.forename: Dorothy G
authors.initials: DG
authors.lastname: Flood
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Reaume
authors.forename: Karen S
authors.initials: KS
authors.lastname: Dorfman
authors.forename: Yin Guo
authors.initials: YG
authors.lastname: Lin
authors.forename: Diane M
authors.initials: DM
authors.lastname: Lang
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Trusko
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
authors.forename: Wim G
authors.initials: WG
authors.lastname: Annaert
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Robert
authors.initials: R
authors.lastname: Siman
authors.forename: Richard W
authors.initials: RW
authors.lastname: Scott
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005260:Female; D018390:Gene Targeting / Q000379:methods; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42)