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Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation
Masihuz Zaman1,2, Shu Yang1,2,3, Ya Huang1,2
1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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 Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble 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 in Alzheimer's disease models. Loss of MDK accelerates amyloid plaque formation and brain inflammation, suggesting MDK has a protective role against Alzheimer's pathology.
Area of Science:
- Neuroscience
- Proteomics
- Molecular Biology
Background:
- Proteomic studies reveal upregulated midkine (MDK) in Alzheimer's disease (AD) brains, correlating with amyloid-beta (Aβ) early in the disease.
- The precise function of MDK in AD pathogenesis remains largely unexplored.
Purpose of the Study:
- To investigate the role of midkine (MDK) in amyloid-beta (Aβ) assembly and Alzheimer's disease (AD) pathology.
- To elucidate the protective or detrimental effects of MDK in AD progression using a mouse model.
Main Methods:
- In vitro assays (Thioflavin T, circular dichroism, electron microscopy, NMR) to assess MDK's effect on Aβ40 and Aβ42 peptide fibril formation.
- Utilized the 5xFAD amyloidosis mouse model, comparing wild-type and Mdk knockout mice.
- Performed comprehensive mass spectrometry-based proteomic profiling of whole and detergent-insoluble brain proteomes.
Main Results:
- MDK protein significantly mitigates the fibril formation of both Aβ40 and Aβ42 peptides.
- Mdk gene knockout in 5xFAD mice led to increased amyloid formation and heightened microglial activation.
- Proteomic analysis revealed accumulation of Aβ, Aβ-correlated proteins, and microglial components in Mdk knockout models.
Conclusions:
- Midkine (MDK) exhibits a protective role by attenuating Aβ assembly and amyloid pathology in Alzheimer's disease.
- MDK deficiency exacerbates amyloidosis and neuroinflammation, highlighting its potential as a therapeutic target.
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