title: Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abeta1-42/43 expression.
abstract: Mutations in presenilin 1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster production of Abeta1-42/43 in FAD patients and transgenic mice. PS1 null mice are embryonic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type human PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indicating that the mutation does not lead to loss of PS1 function during development. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mice does not lead to Abeta1-42/43 increase, whereas expression of human mutant PS1 on murine PS1 null background is sufficient to elevate Abeta1-42/43, supporting a gain-of-function activity as the result of the PS1 mutation.
authors.affiliation: Department of Biochemistry and Physiology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: S
authors.initials: S
authors.lastname: Qian
authors.forename: P
authors.initials: P
authors.lastname: Jiang
authors.forename: X M
authors.initials: XM
authors.lastname: Guan
authors.forename: G
authors.initials: G
authors.lastname: Singh
authors.forename: M E
authors.initials: ME
authors.lastname: Trumbauer
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: H Y
authors.initials: HY
authors.lastname: Chen
authors.forename: L H
authors.initials: LH
authors.lastname: Van de Ploeg
authors.forename: H
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology*; D001921:Brain / Q000002:abnormalities / Q000196:embryology*; D001923:Brain Chemistry / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology; D011247:Pregnancy; D053764:Presenilin-1; D019076:Transgenes / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1