title: Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes.
abstract: Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.
authors.affiliation: Department of Neurology, Allegheny University of the Health Sciences MCP Division, Philadelphia, Pennsylvania 19129, USA. lippa@auhs.edu
authors.forename: C F
authors.initials: CF
authors.lastname: Lippa
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
authors.forename: D M
authors.initials: DM
authors.lastname: Mann
authors.forename: B
authors.initials: B
authors.lastname: Giasson
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: M L
authors.initials: ML
authors.lastname: Schmidt
authors.forename: L E
authors.initials: LE
authors.lastname: Nee
authors.forename: B
authors.initials: B
authors.lastname: O'Connell
authors.forename: D A
authors.initials: DA
authors.lastname: Pollen
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
authors.forename: D
authors.initials: D
authors.lastname: Nochlin
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: N J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis*; D053764:Presenilin-1; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein