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Profiling of the detergent-insoluble proteome of the cortical brain tissues by TMT-LC/LC-MS/MS

ABSTRACT: Mass spectrometry analysis of insoluble proteome from 5xFAD/Mdk-KO mouse brain. This study examines the insoluble protein fraction, focusing on aggregation-prone proteins including Aβ and its associated proteins. The data reveals significant accumulation of Aβ-correlated proteins and microglial components in the absence of MDK, supporting its protective role against amyloid pathology in Alzheimer's disease.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Disease

SUBMITTER: ya huang

LAB HEAD: Junmin Peng

PROVIDER: PXD061104 | Pride | 2025-07-16

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	MDK_Ins_F1.1.pepXML	Pepxml
	MDK_Ins_F1.raw	Raw
	MDK_Ins_F10.1.pepXML	Pepxml
	MDK_Ins_F10.raw	Raw
	MDK_Ins_F11.1.pepXML	Pepxml

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1 - 5 of 81

Publications

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation.

Zaman Masihuz M Yang Shu S Huang Ya Y Yarbro Jay M JM Hao Yanhong Y Wang Zhen Z Liu Danting D Harper Kiara E KE Soliman Hadeer H Hemphill Alex A Harvey Sarah S Pruett-Miller Shondra M SM Stewart Valerie V Tanwar Ajay Singh AS Kalathur Ravi R Grace Christy R CR Turk Martin M Chittori Sagar S Jiao Yun Y Wu Zhiping Z High Anthony A AA Wang Xusheng X Serrano Geidy E GE Beach Thomas G TG Yu Gang G Yang Yang Y Chen Ping-Chung PC Peng Junmin J

bioRxiv : the preprint server for biology 20250320

Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with Aβ since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides in Thioflavin T fluorescence assay, c ...[more]

PMID: 40166321

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Aggregated proteome of MDK model mice

Project description:MDK is a heparin-binding growth factor and found to be the Aβ associated protein. Through aggregated proteome, we aim to identify DE proteins more associated with plaques by MDK knockout.

2025-07-16 | PXD045746 | Pride

Quantitative proteomics of tau and Aβ amyloid in detergent insoluble fractions from Alzheimer’s disease brains

Project description:The two hallmarks of Alzheimer’s disease (AD) are A-amyloid- (A) plaques and neurofibrillary tangles marked by phosphorylated tau. There is compelling evidence that aggregating A drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely there is a growing realization that non-fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Using quantitative proteomics, we find that AD brain sarkosyl-insoluble pellets are greatly enriched with A at almost equimolar levels to N-terminal truncated microtubule binding region (MTBR) isoforms of tau with multiple post-translational modifications (PTMs). The extracted R3-R4 tau peptides are 100-fold higher compared to N-terminus intact tau peptides. Substantial proportions of site-specific phosphorylation at T181 (~ 22 %) and T217 (~ 16 %) along with other PTMs in the proline rich region (PRR) and MTBR indicate a regional susceptibility of PTMs in aggregated tau. Immuno-electron microscopy reveals that co-purified A and tau co-localize to globular non-filamentous aggregates.

2022-06-04 | PXD032372 | Pride

Profiling of the cortical brain proteome in WT, KO, FAD and FAD/KO mice by TMT-LC/LC-MS/MS

Project description:Proteomic analysis of 5xFAD/Mdk-KO mouse brain reveals proteome-wide changes. This study investigates the impact of midkine (MDK) knockout in 5xFAD mouse model using comprehensive mass spectrometry-based whole proteome profiling. The data demonstrates significant alterations in amyloid formation and microglial activation, providing insights into MDK's protective role in Alzheimer's disease pathology.

2025-07-16 | PXD061103 | Pride

Quantitative proteomics of tau and Aβ amyloid in detergent insoluble fractions from Alzheimer’s disease brains

2022-06-04 | PXD032389 | Pride

Whole proteome of MDK model mice

Project description:MDK is a heparin-binding growth factor and found to be the Aβ associated protein. AD mouse model of MDK knockout was established to provide the animal tool to investigate the effect of MDK on AD. Through proteome, we aim to study the Aβ change and identify the DE proteins by MDK knockout to know how MDK affect AD.

2025-07-16 | PXD046539 | Pride

Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease

Project description:It was recently revealed that gut microbiota promote amyloid-beta (Aβ) burden in mouse models of Alzheimer’s disease (AD). However, the underlying mechanisms when using either germ-free (GF) housing conditions or treatments with antibiotics (ABX) remained unknown. In this study, we show that GF and ABX-treated 5x familial AD (5xFAD) mice developed attenuated hippocampal Aβ pathology and associated neuronal loss, and thereby delayed disease-related memory deficits. While Ab production remained unaffected in both GF and ABX-treated 5xFAD mice, we noticed in GF 5xFAD mice enhanced microglial Aβ uptake at early stages of the disease compared to ABX-treated 5xFAD mice. Furthermore, RNA-sequencing of hippocampal microglia from SPF, GF and ABX-treated 5xFAD mice revealed distinct microbiota-dependent gene expression profiles associated with phagocytosis and altered microglial activation states. Taken together, we observed that constitutive or induced microbiota modulation in 5xFAD mice differentially controls microglial Aβ clearance mechanisms preventing neurodegeneration and cognitive deficits.

2020-07-15 | GSE154428 | GEO

Dissecting detergent-insoluble proteome in Alzheimer's disease by improved TMT-MS of high accuracy

Project description:Protein aggregation of amyloid-β (Aβ) peptides and tau are pathological hallmarks of Alzheimer's disease (AD), which are often resistant to detergent extraction and thus enriched in the insoluble proteome. However, additional proteins that co-accumulate in the detergent-insoluble AD brain proteome remain less studied. Here we comprehensively characterized key proteins and pathways in the detergent-insoluble proteome from human AD brain samples by differential extraction, coupled with tandem mass tags labeling and two-dimensional liquid chromatography tandem mass spectrometry (TMT-LC/LC-MS/MS).

2023-10-24 | PXD038381 | Pride

Prior activation state shapes the microglia response to anti-human TREM2 in a mouse model of Alzheimer's disease

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s Disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here we tested whether TREM2 engagement by an agonistic mAb, hT2AB, designated as a surrogate ligand facilitates microglia responses in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control IgG exposed trajectories representative of activated microglial populations including disease-associated microglia (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia transitions. Moreover, Cyc-M and IFN-R microglia were better represented in female than male TREM2CV-5XFAD mice, likely reflecting a greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished the Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which microglia transitions in response to Aβ had already reached their peak. Repeated treatment with a murinized version mT2AB over a 10 days period increased brain content of chemokines in TREM2R47H-5XFAD mice, consistent with microglia expansion and shifts in gene expression patterns. Thus, the impact of hT2AB on microglia responses is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

2020-12-08 | GSE156183 | GEO

Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice

Project description:The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer’s disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.

2025-03-13 | GSE288170 | GEO

Targeted quantification of detergent-insoluble RNA-binding proteins in Alzheimer’s disease reveals disease-specific coaggregation signatures

Project description:Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including Tau and amyloid beta (Aβ) in detergent insoluble fractions from AD brain and that of other dementias. In total, we quantified 870 peptides from 385 detergent-insoluble RNA-binding proteins across 44 cortical tissues including controls, AsymAD, AD, and Parkinson’s Disease (PD). Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and Tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles progressively increased in insolubility across progressive AD stages, whereas the RNA splicing module was decreased specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across neurodegenerative diseases.

2021-03-17 | PXD022144 | Pride

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