Premium
The amyloid plaque proteome in different subtypes of Alzheimer’s disease
Author(s) -
Drummond Eleanor,
Pires Geoffrey,
Kanshin Evgeny,
Askenazi Manor,
Ueberheide Beatrix,
Wisniewski Thomas
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044973
Subject(s) - proteome , amyloid (mycology) , proteomics , alzheimer's disease , biology , pathogenesis , pathology , senile plaques , microbiology and biotechnology , disease , medicine , biochemistry , gene
Background Amyloid plaques contain many proteins in addition to beta amyloid (Aß). Previous studies examining individual plaque‐associated proteins have shown that the presence of these proteins is important: they provide insight into Alzheimer’s disease (AD) pathogenesis, and they are potential biomarkers and/or therapeutic targets for AD. However, a comprehensive analysis of all proteins enriched in amyloid plaques has not yet been done. Therefore, the aim of this study was to use an unbiased proteomic approach to identify all proteins consistently enriched in amyloid plaques in different subtypes of Alzheimer’s disease. Method We used label‐free quantitative mass spectrometry to identify all proteins significantly enriched in microdissected amyloid plaques in comparison to surrounding, non‐plaque tissue in two subtypes of AD; sporadic early onset AD (EOAD; age at death <65; n = 5) and Down syndrome with AD (DS; n = 5). Validation was performed using immunohistochemistry and by comparison with published proteomics databases. Result 116 proteins were consistently enriched in plaques in EOAD and DS in addition to Aß. The five most highly enriched proteins in plaques were the same in both subtypes of AD; COL25A1 (136 fold enriched in plaques), SMOC1 (87 fold enriched), MDK (59 fold enriched), NTN1 (55 fold enriched), and HTRA1 (49 fold enriched). Amyloid plaques were most significantly enriched in vesicle proteins (predominantly endosomal/lysosomal proteins; enrichment FDR = 5.71 × 10 −19 ), therefore suggesting that the endosomal/lysosomal system may have an important role in amyloid plaque formation. We also identified 53 novel proteins enriched in plaques: 12 of these proteins have been previously associated with either Aß or APP, but not yet known to be present in plaques, while 41 of these proteins have not yet been associated with Aß. Immunohistochemistry validated the enrichment of selected novel plaque proteins such as all ERM family members (ezrin, radixin, moesin), which interact with the actin cytoskeleton and have important roles in endosome transport and maturation. Conclusion Amyloid plaques are enriched in >100 proteins in addition to Aß. We have identified many novel amyloid plaque proteins, which may be potential therapeutic targets and/or biomarkers for AD.