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

Carol F. Lippa, Hideo Fujiwara, David M.A. Mann, Benoit Giasson, Minami Baba, Marie L. Schmidt, Linda E. Nee, Brendan O'Connell, Dan A. Pollen, Peter St. George-Hyslop, Bernardino Ghetti, David Nochlin, Thomas D. Bird, Nigel J. Cairns, Virginia M.Y. Lee, Takeshi Iwatsubo, John Q. Trojanowski

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Abstract

Missense mutations in the α-synuclein gene cause familial Parkinson's disease (PD), and α-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 α-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 α-, β-, and γ-synuclein. LBs were detected with α- but not β- or γ-synuclein antibodies in 22% of FAD brains, and α-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 α-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, α-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of α-synuclein was reduced compared with control brains. The presence of α-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble α- 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.

Original languageEnglish (US)
Pages (from-to)1365-1370
Number of pages6
JournalAmerican Journal of Pathology
Volume153
Issue number5
DOIs
StatePublished - Nov 1998

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Lippa, C. F., Fujiwara, H., Mann, D. M. A., Giasson, B., Baba, M., Schmidt, M. L., Nee, L. E., O'Connell, B., Pollen, D. A., St. George-Hyslop, P., Ghetti, B., Nochlin, D., Bird, T. D., Cairns, N. J., Lee, V. M. Y., Iwatsubo, T., & Trojanowski, J. Q. (1998). Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. American Journal of Pathology, 153(5), 1365-1370. https://doi.org/10.1016/S0002-9440(10)65722-7