Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes.
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.
Lippa
C F
CF
Department of Neurology, Allegheny University of the Health Sciences MCP Division, Philadelphia, Pennsylvania 19129, USA. lippa@auhs.edu
Fujiwara
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Mann
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Giasson
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Baba
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Schmidt
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Nee
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O'Connell
B
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Pollen
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St George-Hyslop
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Ghetti
B
B
Nochlin
D
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Bird
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Cairns
N J
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Lee
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Iwatsubo
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Trojanowski
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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
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