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Midkine Attenuates Aβ Fibril Assembly and AmyloidPlaque Formation
Junmin Peng1, Masihuz Zaman1, Shu Yang1
1St Jude Children's Research Hospital.
Abstract:
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, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdkgene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and aggregated proteome in these mouse models indicates significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimer's disease.
Insights
Midkine (MDK) protein reduces amyloid-beta (Aβ) assembly and amyloid plaque formation in Alzheimer's disease models. MDK knockout exacerbates amyloid pathology and microglial activation, suggesting a protective role for MDK.
Area of Science:
- Neuroscience
- Proteomics
- Molecular Biology
Background:
- Proteomic studies in Alzheimer's disease (AD) brains reveal upregulated proteins like midkine (MDK).
- The function of MDK in AD pathogenesis, particularly its association with amyloid-beta (Aβ) from early stages, remains unclear.
Purpose of the Study:
- To investigate the role of midkine (MDK) in amyloid-beta (Aβ) assembly and aggregation.
- To determine the impact of MDK on Alzheimer's disease pathology using the 5xFAD mouse model.
Main Methods:
- In vitro assays (Thioflavin T, circular dichroism, electron microscopy, NMR) to assess MDK's effect on Aβ40 and Aβ42 fibril formation.
- Genetic manipulation (Mdk knockout) in the 5xFAD mouse model to study in vivo effects.
- Mass spectrometry-based proteomic profiling of whole and aggregated proteomes in mouse models.
Main Results:
- MDK protein was found to mitigate the fibril formation of Aβ40 and Aβ42 peptides.
- Mdk gene knockout in 5xFAD mice led to increased amyloid formation and heightened microglial activation.
- Proteomic analysis revealed significant accumulation of Aβ, Aβ-correlated proteins, and microglial components in Mdk knockout models.
Conclusions:
- Midkine (MDK) plays a protective role by attenuating amyloid-beta (Aβ) assembly and amyloid pathology in Alzheimer's disease.
- MDK influences amyloid formation and modulates microglial responses in the context of AD.
- These findings highlight MDK as a potential therapeutic target for counteracting Alzheimer's disease progression.
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