title: The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology.
abstract: Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at the C-terminus of A beta to favor deposition of A beta 42.
authors.affiliation: Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lemere
authors.forename: F
authors.initials: F
authors.lastname: Lopera
authors.forename: K S
authors.initials: KS
authors.lastname: Kosik
authors.forename: C L
authors.initials: CL
authors.lastname: Lendon
authors.forename: J
authors.initials: J
authors.lastname: Ossa
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: L
authors.initials: L
authors.lastname: Madrigal
authors.forename: L
authors.initials: L
authors.lastname: Hincapie
authors.forename: J C
authors.initials: JC
authors.lastname: Arango
authors.forename: D C
authors.initials: DC
authors.lastname: Anthony
authors.forename: E H
authors.initials: EH
authors.lastname: Koo
authors.forename: A M
authors.initials: AM
authors.lastname: Goate
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: J C
authors.initials: JC
authors.lastname: Arango
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001923:Brain Chemistry; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D003062:Codon / Q000235:genetics; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000473:pathology; D017354:Point Mutation; D053764:Presenilin-1
chemical_list: D016229:Amyloid beta-Peptides; D003062:Codon; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1