Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes - PubMed (original) (raw)

. 1998 Nov;153(5):1365-70.

doi: 10.1016/s0002-9440(10)65722-7.

H Fujiwara, D M Mann, B Giasson, M Baba, M L Schmidt, L E Nee, B O'Connell, D A Pollen, P St George-Hyslop, B Ghetti, D Nochlin, T D Bird, N J Cairns, V M Lee, T Iwatsubo, J Q Trojanowski

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

C F Lippa et al. Am J Pathol. 1998 Nov.

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.

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Figures

Figure 1.

Figure 1.

Low-magnification (A) and high-magnification (B) photomicrographs of numerous α-synuclein-positive LBs and occasional (arrow) Lewy neurites (C). A nigral LB stained with the α-synuclein antibody is demonstrated in D. E and F show LBs examined by double-label immunohistochemistry to demonstrate α-synuclein-positive (pink) LBs and tau-positive (brown; see arrows) NFTs in different (E) or the same (F) neurons. A section of the amygdala from a normal control contains no α-synuclein-positive LBs or other lesions (G). Immuno-EM demonstrates an α-synuclein-positive LB in an amygdala neuron of a PS-1 patient (H). LB filaments are decorated by the antibody to α-synuclein. Scale bars, 30 μm (A and G), 10 μm (C), and 20 μm (B and D–F), and 200 μm (H).

Figure 2.

Figure 2.

Western blot analysis performed with MAb LB509 demonstrated high molecular mass aggregates of α-synuclein in the amygdala from FAD patients with PS-1 mutations. Amygdalas from control and FAD patients were fractionated as described in Materials and Methods. A: α-Synuclein in the high-salt-soluble fractions from the amygdala of three FAD cases (FAD1-3) compared with the amygdala from two control cases (C1-2). B: α-Synuclein in the high-salt-insoluble, Triton X-100-soluble fractions. C: α-Synuclein in formic-acid-extractable fractions. Five microliters of high-salt-insoluble, Triton X-100-soluble extracts or 10 μl of formic-acid-extractable extracts was loaded in each lane, respectively. The Western blots developed from high-salt-soluble and Triton X-100-soluble extracts were exposed to film for the same length of time, whereas the blot developed from formic-acid-extractable samples was exposed approximately five times longer.

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