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

Am J Pathol. 1998 Nov;153(5):1365-70. doi: 10.1016/s0002-9440(10)65722-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics*
  • Blotting, Western
  • Brain / pathology*
  • Female
  • Humans
  • Immunohistochemistry
  • Lewy Bodies / chemistry*
  • Lewy Bodies / pathology
  • Male
  • Membrane Proteins / genetics*
  • Microscopy, Immunoelectron
  • Middle Aged
  • Mutation
  • Nerve Tissue Proteins / analysis*
  • Presenilin-1
  • Synucleins
  • alpha-Synuclein
  • gamma-Synuclein


  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • gamma-Synuclein