Lewy bodies contain altered α-synuclein in brains of many familiar Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes

被引:441
作者
Lippa, CF
Fujiwara, H
Mann, DMA
Giasson, B
Baba, M
Schmidt, ML
Nee, LE
O'Connell, B
Pollen, DA
George-Hyslop, PS
Ghetti, B
Nochlin, D
Bird, TD
Cairns, NJ
Lee, VMY
Iwatsubo, T
Trojanowski, JQ
机构
[1] Allegheny Univ Hlth Sci, Dept Neurol, MCP Div, Philadelphia, PA 19129 USA
[2] Univ Tokyo, Dept Neuropathol & Neurosci, Tokyo, Japan
[3] Univ Manchester, Dept Pathol Sci, Manchester, Lancs, England
[4] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[5] NINDS, Family Studies Unit, Ctr Clin, Bethesda, MD 20892 USA
[6] Univ Massachusetts, Med Ctr, Dept Neurol, Worcester, MA 01655 USA
[7] Univ Toronto, Dept Med Neurol, Toronto, ON, Canada
[8] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[9] Indiana Univ, Med Ctr, Dept Pathol, Indianapolis, IN USA
[10] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA
[11] VA Med Ctr, Dept Neurol, Seattle, WA USA
[12] Univ Washington, Sch Med, Seattle, WA USA
[13] Inst Psychiat, London, England
关键词
D O I
10.1016/S0002-9440(10)65722-7
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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.
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页码:1365 / 1370
页数:6
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