Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comprehensive Profiling of Aβ40 and Aβ42 Fibril-Interacting Proteins Reveals PRKCG as a Drug-Targetable Regulator of Amyloidogenesis in Alzheimer’s Disease

ABSTRACT: Proteins associated with amyloid-β (Aβ) pathology are critical biomarkers and potential therapeutic targets for Alzheimer’s disease (AD). Previous studies analyzing Aβ plaque composition relied on micro-dissected plaques from tissue samples. Here, we aimed to study the proteome associated with Aβ40- and Aβ42-plaques to identify protein constituents of Aβ plaques—actual Aβ40- and Aβ42-fibril interactors—, which might drive Aβ plaque development. Biotinylated-Aβ40, or -Aβ42, were incubated to form fibrils, with scrambled peptides used as control, and subjected to pull-down assays using protein extracts from AD and control prefrontal cortex tissues. Aβ-interacting proteins were identified by proteomics. Their dysregulation was assessed in AD tissue samples and a cellular AD model by WB, immunocytochemistry, in silico, and immunohistochemistry. We identified 185 and 874 proteins associated with Aβ40- and Aβ42-fibrils, respectively, with 78 in common. Sixteen were validated as interactors by WB and ex vivo as components of Aβ plaques by IF, displaying altered expression in AD and supporting a functional role for PRKCG in amyloidogenesis, as its modulation alters Aβ fibril formation. This study expands the Aβ plaque-associated proteome characterization, identifies novel fibril interactors, and highlight potential therapeutic targets, as the modulation of PRKCG prevent or reduce Aβ plaque formation in AD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Ana Montero Calle

LAB HEAD: Rodrigo Barderas

PROVIDER: PXD061100 | Pride | 2026-01-24

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	13Fibras_Ab40_H_R1.raw	Raw
	13Fibras_Ab40_H_R2.raw	Raw
	13Fibras_Ab40_H_R3.raw	Raw
	14Fibras_Ab40_BrV_R1.raw	Raw
	14Fibras_Ab40_BrV_R2.raw	Raw

Items per page:

1 - 5 of 40

Similar Datasets

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

Project description:A defining hallmark of Alzheimer's disease (AD) is the synaptic aggregation of the amyloid beta (Aβ) peptide. In vivo, Aβ production results in a diverse mixture of variants, of which Aβ40, Aβ42, and Aβ43 are profusely present in the AD brain, and their relative abundance is recognised to play a role in disease onset and progression. Nonetheless, the occurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerisation and the subsequent effects on Aβ aggregation remain elusive and were investigated here. Using thioflavin-T (ThT) monitored aggregation assays and native mass spectrometry coupled to ion mobility analysis (IM-MS), we first show that all Aβ peptides are aggregation-competent and self-assemble into homo-oligomers with distinct conformational populations, which are more pronounced between Aβ40 than the longer variants. ThT assays were then conducted on binary mixtures of Aβ variants, revealing that Aβ42 and Aβ43 aggregate independently from Aβ40, but significantly speed-up Aβ40 fibrillation. Aβ42 and Aβ43 were observed to aggregate concurrently and mutually accelerate fibril formation, which likely involves hetero-oligomerisation. Accordingly, native MS analysis revealed pairwise oligomerisation between all variants, with the formation of heterodimers and heterotrimers. Interestingly, IM-MS indicates that hetero-oligomers containing longer Aβ variants are enriched in conformers with lower collision-cross sections when compared to their homo-oligomer counterparts. This suggests that Aβ42 and Aβ43 are capable of remodelling oligomer structure towards a higher compaction level. Altogether, our findings provide a mechanistic description for the hetero-oligomerisation of Aβ variants implicated in AD, contributing to rationalising their in vivo proteotoxic interplay.

2025-01-31 | PXD057653 | Pride

Expression data from Saccharomyces cerevisiae

Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Oligomers of Amyloid-β peptides (Aβ) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aβ associated with AD are Aβ40 and Aβ42, the latter being more prone to form oligomers and toxic. Humanized yeast models are currently applied to unravel the cellular mechanisms behind Aβ toxicity. Here, we took a systems biology approach to study two yeast AD models which expressed either Aβ40 or Aβ42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected the chronological lifespan and reduced confounding effects of variations during cell growth. Reduced growth rates and biomass yields were observed upon expression of Aβ42, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aβ42 expressing cells, which matched with observed aberrant fragmented mitochondrial structures. Genome-wide expression levels analysis showed that Aβ42 expression triggers strong ER stress and unfolded protein responses (UPR). Expression of Aβ40 induced only mild ER stress, leading to activation of UPR target genes that cope with misfolded proteins, which resulted in hardly affected physiology. The combination of well-controlled cultures and AD yeast models strengthen our understanding of how cells translate different levels of Aβ toxicity signals into particular cell fate programs, and further enhance their role as a discovery platform to identify potential therapies.

2017-08-31 | GSE94793 | GEO

Excitatory and inhibitory neurons accumulate distinct Ab plaques in mouse models of APP overexpression

Project description:Amyloid plaque heterogeneity is a hallmark of Alzheimer's disease (AD), yet the mechanisms governing plaque diversity and its relationship to disease progression remain poorly understood. Although both diffuse and neuritic plaques are present in AD brain tissue, we do not know how these distinct conformations arise or influence pathological outcomes. Here, we developed transgenic mouse models expressing identical APP constructs in either glutamatergic or GABAergic neurons to investigate how cellular context shapes amyloid pathology. This approach revealed that the cellular source of APP influences both the biochemical composition and structural characteristics of resulting Aβ deposits. APP expressed in GABAergic neurons generated exclusively diffuse plaques with elevated Aβ42/Aβ40 ratios that failed to induce gliosis, while glutamatergic expression produced primarily neuritic plaques surrounded by activated microglia. Differences in deposit characteristics appeared to arise from fundamental variations in APP processing between excitatory and inhibitory neurons. Moreover, only neuritic plaques generated by glutamatergic neurons caused behavioral deficits, while diffuse plaques from GABAergic neurons did not impair cognition despite substantial amyloid burden. These findings may provide new insight into the mechanisms underlying amyloid heterogeneity in AD and suggest that plaque conformation, rather than simply amyloid load, may influence cognitive trajectories. snRNA-seq revealed that microglia from the excitatory models showed many DAM genes were upregulated, which were absent in the inhibitory model. The data also revealed there were no changes in expression of key APP processing enzymes between excitatory or inhibitory neurons in each model.

2026-01-07 | GSE292822 | GEO

Phagocytes as Plaque Catalysts: Human Macrophages Generate Seeding-Competent Aβ42 Fibrils with Cross-Seeding Activity

Project description:The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer’s disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells—including differentiated THP-1 macrophages and iPSC-derived microglia—are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, exhibiting heightened seeding activity and the ability to cross-seed tau aggregation, a key driver of AD progression. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of TREM2, a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models, positioning this system as a tractable, human-relevant platform to dissect the interplay between Aβ aggregation, innate immunity, and genetic susceptibility. Our findings suggest that macrophages and microglia play a dual role in AD, acting both as responders and inadvertent catalysts of pathogenic amyloid formation, with implications for early therapeutic intervention.

2026-02-13 | GSE319445 | GEO

UBB+1-induced activation of autophagy reduces cytotoxicity of amyloid-β in yeast

Project description:UBB+1 is a mutated version of ubiquitin B caused by a transcriptional frameshift. The accumulation of UBB+1, has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer’s disease (AD) is the most common form of neurodegeneration and accumulation of amyloid β (Aβ) in the brain is a prominent neuropathological feature of AD. In our previous study, we found that low expression of UBB+1 could protect cells against several stresses during chronological aging. Here, we applied the genome-wide expression analyses and found that low UBB+1 expression activated the autophagy pathway. Low UBB+1 expression was shown to upregulate vacuolar activity and promote transport of the ATG8p (autophagic marker) to the vacuole. To further study the effects, we expressed low level of UBB+1 in our humanized yeast Aβ models with the expression of either Aβ42 or Aβ40. Interestingly, the co-expression of UBB+1 with Aβ42 or Aβ40 showed a reduction of intracellular Aβ levels and increased chronological life span. In the autophagy deficient mutant background (atg1∆), the intracellular Aβ levels were not affected by UBB+1 expression. Our findings suggest a mechanism of UBB+1 action in reducing intracellular levels of Aβ.

2021-03-12 | GSE129688 | GEO

Cultures of hiPS cells and their differentiation into neuronal cells

Project description:In order to identify endogenous factors that modulate Aβ production, we performed a transcriptome analysis on neuronal cells derived from human induced pluripotent stem cells (hiPS) because these cells changed the Aβ production during neuronal differentiation. When the expression of APP and the ratio Aβ42/40 of the secreted proteins were measured at days 38, 45, and 52 during differentiation, both APP expression and the secretion of Aβ40 and Aβ42 at days 45 and 52 were significantly increased compared to those at day 38. Furthermore, the ratio of Aβ42/40 was dramatically reduced at days 45 and 52 compared to that at day 38. We hypothesized that transcriptional changes during the differentiation into neuronal cells may affect APP production and/or processing. To test this hypothesis, we performed microarray analyses using three independent neuronal cell cultures that were differentiated from each of three hiPS cells, namely 201B7, 253G4, and AD4F-1 (nine cell lines in total). Total RNA was prepared at three differentiation time points (days 38, 45, and 52) and subjected to an Affymetrix Gene Chip Human Exon 1.0 ST array. Compare between samples from 38-day cultures and samples from 45- and 52-day cultures.

2020-01-24 | E-MTAB-7852 | biostudies-arrayexpress

Transcriptome sequencing of hippocampal tissue of APP/PS1 mice treated with rotating magnetic field for 12 months

Project description:Amyloid beta (Aβ) monomers aggregate to form fibrils and amyloid plaques, which is one of the important mechanisms in the pathogenesis of Alzheimer's disease (AD). Since the Aβ1-42 aggregation has prominent role in plaque formation, which eventually lead to the patient's brain lesions and cognitive impairment, an increasing number of studies have been devoted to reduce Aβ aggregation process to slow down AD progression. Since the diphenylalanine (FF) sequence is critical for amyloid aggregation, and it has been shown that magnetic fields can affect the alignment of peptide assembly due to the diamagnetic anisotropy of aromatic rings, here we used a moderate-intensity rotating magnetic field (RMF) to explore its effect on Aβ aggregation and AD pathogenesis. Our data showed that RMF can directly inhibit Aβ amyloid fibril formation and reduce Aβ-induced cytotoxicity on neural cells in vitro. Using the AD mouse model APP/PS1, we found that the RMF can restore their motor ability to the healthy control level. Their cognitive impairments, including exploration ability, spatial and non-spatial memory abilities, were also significantly alleviated. Tissue examinations reveal that RMF has reduced amyloid plaque accumulation, attenuated microglial activation ,and reduced oxidative stress in the APP/PS1 mouse brain. Therefore, our data demonstrate the great potential of RMF to be developed as a non-invasive, high-penetration physical approach to be applied in the treatment of AD.

2024-06-06 | GSE269222 | GEO

Extracellular matrix remodeling enhancing astrocyte lysosome pathway to reverse memory defected in Alzheimer’s disease

Project description:Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer’s disease (AD) risk, but its functions are not fully understood. Here, we found that medial prefrontal cortex (mPFC) injection with chondroitinase ABC (ChABC) to remodel ECM reverses short-term memory loss and reduces Aβ deposition in 5xFAD mice. ECM remodeling also reactivates astrocytes, untangles aggrecan’s entanglement with amyloid-beta (Aβ) plaques, and encourages astrocyte recruitment to the surrounding plaques. ECM remodeling promotes astrocyte phagocytosis of Aβ plaque by activating the astrocyte phagocytosis receptor mertk and astrocytic vesicle circulation. Importantly, ECM remodeling enhances the autophagy-lysosome pathway in astrocytes to mediate Aβ clearance and alleviate AD pathology. Our work thus discovers a cellular mechanism to remodel the ECM to active astrocyte autophagic lysosomal pathway alleviation AD pathology. It may represent a potential therapeutic strategy and serve as a hallmark for treating AD.

2024-10-17 | PXD046784 | Pride

Loss of ATG7 in Microglia Impairs UPR, Triggers Ferroptosis and Weakens Amyloid Pathology Control [bulk RNA-seq]

Project description:Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer’s Disease (AD) is to contain proteotoxic amyloid β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ build-up, UPR reduction and increase oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation as they age.

2025-01-30 | GSE286095 | GEO

Loss of ATG7 in Microglia Impairs UPR, Triggers Ferroptosis and Weakens Amyloid Pathology Control [scRNA-seq]

2025-01-30 | GSE286094 | GEO