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Dissecting the Structural Organization of Multiprotein Amyloid Aggregates Using a Bottom-Up Approach.
Chaudhary, Himanshu; Meister, Sebastian W; Zetterberg, Henrik; Löfblom, John; Lendel, Christofer.
Afiliação
  • Chaudhary H; Department of Chemistry, KTH Royal Institute of Technology, Stockholm SE-100 44, Sweden.
  • Meister SW; Department of Protein Science, KTH Royal Institute of Technology, Stockholm SE-100 44, Sweden.
  • Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal SE-413 90, Sweden.
  • Löfblom J; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal SE-413 90, Sweden.
  • Lendel C; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
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.
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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

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