The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome.
Alzheimer Disease
/ pathology
Amyloid beta-Peptides
/ metabolism
Brain
/ pathology
Down Syndrome
/ pathology
Glycoproteins
High-Temperature Requirement A Serine Peptidase 1
/ metabolism
Humans
Intercellular Signaling Peptides and Proteins
Plaque, Amyloid
/ pathology
Proteome
/ metabolism
Pyrrolidonecarboxylic Acid
Alzheimer’s disease
Amyloid beta
Amyloid plaques
Down syndrome
Early onset
Mass spectrometry
Proteomics
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
13 04 2022
13 04 2022
Historique:
received:
31
01
2022
accepted:
28
03
2022
entrez:
14
4
2022
pubmed:
15
4
2022
medline:
16
4
2022
Statut:
epublish
Résumé
Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC-MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.
Identifiants
pubmed: 35418158
doi: 10.1186/s40478-022-01356-1
pii: 10.1186/s40478-022-01356-1
pmc: PMC9008934
doi:
Substances chimiques
Amyloid beta-Peptides
0
Glycoproteins
0
Intercellular Signaling Peptides and Proteins
0
OLFML3 protein, human
0
Proteome
0
High-Temperature Requirement A Serine Peptidase 1
EC 3.4.21.-
HTRA1 protein, human
EC 3.4.21.-
Pyrrolidonecarboxylic Acid
SZB83O1W42
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
53Subventions
Organisme : NIH HHS
ID : S10 OD010582
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066512
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG056850
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG060882
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG058267
Pays : United States
Informations de copyright
© 2022. The Author(s).
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