Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes

TLDR

We have combined Purpose and Mechanism in one label. But the label says [Purpose, Mechanism] in one line. The content: "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." So Purpose: "The study aims to determine whether alpha‑synuclein is a component of Lewy bodies in familial Alzheimer’s disease patients with presenilin or amyloid precursor protein mutations." Mechanism: "The authors used antibodies against alpha-, beta-, and gamma‑synuclein to examine Lewy bodies in these patients." That seems fine. Summarize: 22% of FAD brains had alpha-synuclein-positive LBs, most numerous in amygdala, some co-localized with tau tangles; 63% of amygdala samples had them; they may be more common than previously reported; immunoelectron microscopy showed alpha-synuclein in filaments; Western blot showed reduced solubility; no association with specific mutation; suggests insoluble alpha-synuclein aggregates into filaments forming LBs, possibly compromising neuron function.

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.