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The proteome of human amyloid beta oligomers

ABSTRACT: Amyloid β (Aβ) oligomers are thought to play an important role in the onset and progression of Alzheimer’s disease (AD). Several oligomer-binding proteins have been implicated in mechanisms leading to AD pathology. Such proteins could provide insights into the pathways involved in the disease process of AD and might reveal novel targets for disease-modifying therapy approaches. Here, we separated different native Aβ assemblies in brain homogenates of human AD post mortem tissue by density gradient centrifugation, then isolated Aβ-containing complexes by co-immunoprecipitation. Mass spectrometry of immunoprecipitated proteins with label-free quantification (LFQ) showed numerous significant changes between AD and control samples, confirming familiar binding proteins and also indicating putative new interactors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Gereon Poschmann

LAB HEAD: Gereon Poschmann

PROVIDER: PXD053759 | Pride | 2026-04-07

REPOSITORIES: Pride

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			Action	DRS
	20210805_ad_related_sequences.fasta	Fasta
	20220118_P02649_ApoE.fasta	Fasta
	F9_10_AD1.mzML	Mzml
	F9_10_AD1.mzid.gz	Mzid
	F9_10_AD1.raw	Raw

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Publications

The Proteome of Human Amyloid Beta Oligomers.

Kass Bettina B Poschmann Gereon G Demir Fatih F Huesgen Pitter P Stühler Kai K Kutzsche Janine J Willbold Dieter D

Biochemistry 20260114 3

Amyloid beta (Aβ) oligomers are thought to play an important role during development and progression of Alzheimer's disease (AD). Previously, we determined the Aβ oligomer concentrations in various AD mouse models and in human brain tissues of former AD patients. Here, we investigate which proteins are part of these Aβ oligomers, apart from Aβ itself. Because several oligomer-associated proteins have been implicated in mechanisms leading to AD pathology, identification of the Aβ oligomer proteom ...[more]

PMID: 41532798

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The proteome of APP/PS1 mouse amyloid beta oligomers

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2026-04-07 | PXD053785 | Pride

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The diphenylpyrazol compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology.

Project description:Alzheimer’s disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer’s disease, when given orally before or after the onset of pathology. At the mechanistic level we provide evidence that anle138b blocks the formation of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further.

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Oligomeric human Aβ1-42 inhibits antigen presentation

Project description:The goal of this study is to investigate the involvement of inflammation in Alzheimer’s disease (AD) and to clarify the signaling pathways involved in the presence of beta-amyloidosis, a hallmark of AD pathogenesis, to help identifying potential targets for therapy. To do that, we isolated bone marrow-derived progenitor cells from femurs, tibiae and hip bones of non-transgenic C57BL/6 mice according to established protocols , and we maturated them with LPS. To obtain an unbiased view of gene regulation in mouse bone marrow-derived dendritic cells (BM-DCs) exposed to pre-aggregated beta-amyloid peptide (Aβ) oligomers, we analyzed the transcriptome of untreated immature control BM-DCs (‘Ctrl’), LPS-treated BM-DCs (’LPS’), Aβ1-42 oligomer-treated BM-DCs (‘Aβ‘) and BM-DCs treated with Aβ1-42 oligomers and LPS (‘Aβ+LPS‘) via explorative RNA-sequencing.

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Cross interactions of Aβ peptides implicated in Alzheimer’s disease shape amyloid oligomer structures and aggregation

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2025-01-31 | PXD057653 | Pride

Transcriptomic and functional analysis of Ab1-42 oligomer-stimulated human monocyte-derived microglia-like cells

Project description:Dysregulation of microglial function contributes to Alzheimer’s disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimer’s microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with Aβ clearance. Aβ oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to Aβ oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNFα. In contrast, the Ab1-42 oligomers did not induce an inflammatory profile or a classical HAM or DAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the Aβ1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that Aβ1-42 oligomers may trigger a protective response both in vitro and in vivo.

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Project description:Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases that regulate cellular homeostasis in a multifactorial manner. Although alterations in SIRT signaling are evidenced in both olfactory dysfunction and Alzheimer’s disease (AD), the specific role of sirtuin 3 (SIRT3) in olfactory metabolism remains unknown. Here, we have evidenced a partial interdependency between SIRT3 and SIRT5 deacetylase members in human nasal epithelial cell cultures (hNECs). A multi-omic integrative approach applied to conditions of SIRT3 silencing or overexpression revealed that hNEC metabolism is markedly more sensitive to reduced SIRT3 levels, identifying specific transcripts and phosphorylation sites belonging to inflammatory and redox mediators that are tightly regulated by SIRT3 in hNECs. Following exposure to oligomeric Aβ peptide, phosphoproteomic alterations promoted an activation trend of stress-induced senescence and apoptotic signaling in SIRT3-silenced hNECs, whereas induced activation of mitotic phase–related pathways, Hippo signaling, and glycogen metabolism were evidenced in SIRT3-overexpressing hNECs. From a translational point of view, a dissimilar sex-dependent profile in serum SIRT protein levels (SIRT1 and SIRT6) was observed across multiple neurological disorders including AD, mixed dementia, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. These data shed new light on novel SIRT-dependent mechanisms associated with neurodegeneration, underscoring that the maintenance of optimal SIRT3 protein levels may partially counteract the detrimental effects induced by Aβ oligomers in AD at olfactory level.

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