Dissecting the Structural Organization of Multiprotein Amyloid Aggregates Using a Bottom-Up Approach.
ACS Chem Neurosci
; 11(10): 1447-1457, 2020 05 20.
Article
em En
| MEDLINE
| ID: mdl-32315153
Deposition of fibrillar amyloid ß (Aß) in senile plaques is a pathological signature of Alzheimer's disease. However, senile plaques also contain many other components, including a range of different proteins. Although the composition of the plaques can be analyzed in post-mortem tissue, knowledge of the molecular details of these multiprotein inclusions and their assembly processes is limited, which impedes the progress in deciphering the biochemical mechanisms associated with Aß pathology. We describe here a bottom-up approach to monitor how proteins from human cerebrospinal fluid associate with Aß amyloid fibrils to form plaque particles. The method combines flow cytometry and mass spectrometry proteomics and allowed us to identify and quantify 128 components of the captured multiprotein aggregates. The results provide insights into the functional characteristics of the sequestered proteins and reveal distinct interactome responses for the two investigated Aß variants, Aß(1-40) and Aß(1-42). Furthermore, the quantitative data is used to build models of the structural organization of the multiprotein aggregates, which suggests that Aß is not the primary binding target for all the proteins; secondary interactions account for the majority of the assembled components. The study elucidates how different proteins are recruited into senile plaques and establishes a new model system for exploring the pathological mechanisms of Alzheimer's disease from a molecular perspective.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Alzheimer
/
Amiloidose
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
ACS Chem Neurosci
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Suécia