Dataset Information

Molecular subtypes of Alzheimer's disease.

ABSTRACT: Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid ? (A?) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that A? assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of A? species. These differences affect the physicochemical properties of A? assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. A?-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated A?. We found that brain homogenates from AD patients with different molecular profiles of A? are able to induce distinct patterns of A?-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of A? peptides into different A? seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.

SUBMITTER: Di Fede G

PROVIDER: S-EPMC5818536 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Molecular subtypes of Alzheimer's disease.

Di Fede Giuseppe G Catania Marcella M Maderna Emanuela E Maderna Emanuela E Ghidoni Roberta R Benussi Luisa L Tonoli Elisa E Giaccone Giorgio G Moda Fabio F Paterlini Anna A Campagnani Ilaria I Sorrentino Stefano S Colombo Laura L Kubis Adriana A Bistaffa Edoardo E Ghetti Bernardino B Tagliavini Fabrizio F

Scientific reports 20180219 1

Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can cor ...[more]

PMID: 29459625

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Project description:BackgroundProtein glycosylation has been confirmed to be involved in the pathological mechanisms of Alzheimer's disease (AD); however, there is still a lack of systematic analysis of the immune processes mediated by protein glycosylation-related genes (PGRGs) in AD.Materials and methodsTranscriptomic data of AD patients were obtained from the Gene Expression Omnibus database and divided into training and verification datasets. The core PGRGs of the training set were identified by weighted gene co-expression network analysis, and protein glycosylation-related subtypes in AD were identified based on k-means unsupervised clustering. Protein glycosylation scores and neuroinflammatory levels of different subtypes were compared, and functional enrichment analysis and drug prediction were performed based on the differentially expressed genes (DEGs) between the subtypes. A random forest model was used to select important DEGs as diagnostic markers between subtypes, and a line chart model was constructed and verified in other datasets. We evaluated the differences in immune cell infiltration between the subtypes through the single-sample gene set enrichment analysis, analyzed the correlation between core diagnostic markers and immune cells, and explored the expression regulation network of the core diagnostic markers.ResultsEight core PGRGs were differentially expressed between the training set and control samples. AD was divided into two subtypes with significantly different biological processes, such as vesicle-mediated transport in synapses and neuroactive ligand-receptor interactions. The high protein glycosylation subtype had a higher level of neuroinflammation. Riluzole and sulfasalazine were found to have potential clinical value in this subtype. A reliable construction line chart model was constructed based on nine diagnostic markers, and SERPINA3 was identified as the core diagnostic marker. There were significant differences in immune cell infiltration between the two subtypes. SERPINA3 was found to be closely related to immune cells, and the expression of SERPINA3 in AD was found to be regulated by a competing endogenous RNA network that involves eight long non-coding RNAs and seven microRNAs.ConclusionProtein glycosylation and its corresponding immune process play an important role in the occurrence and development of AD. Understanding the role of PGRGs in AD may provide a new potential therapeutic target for AD.

Dataset Information

Molecular subtypes of Alzheimer's disease.

Publications

Molecular subtypes of Alzheimer's disease.

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