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Midkine attenuates amyloid-β fibril assembly and plaque formation
Masihuz Zaman1,2, Shu Yang1,2,3, Ya Huang1,2
1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract:
Proteomic profiling of Alzheimer disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with amyloid-β (Aβ) from 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 according to thioflavin T fluorescence, circular dichroism, negative-stain electron microscopy and nuclear magnetic resonance analyses. Knockout of the Mdk gene in 5xFAD increased amyloid formation and microglial activation in the brain. Further comprehensive mass-spectrometry-based profiling of the whole proteome and detergent-insoluble proteome in these mouse models indicated 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 AD.
Insights
Midkine (MDK) protein reduces amyloid-beta (Aβ) assembly and amyloid plaque formation in Alzheimer disease models. MDK deficiency worsens amyloid pathology and microglial activation, indicating a protective role for MDK.
Area of Science:
- Neuroscience
- Proteomics
- Molecular Biology
Background:
- Alzheimer disease (AD) brains show elevated levels of understudied proteins like midkine (MDK).
- MDK is upregulated and correlates with amyloid-beta (Aβ) from early AD stages, but its function remains unclear.
Purpose of the Study:
- To investigate the role of midkine (MDK) in amyloid-beta (Aβ) assembly and amyloid formation in Alzheimer disease (AD).
- To determine the impact of MDK deficiency on amyloid pathology and neuroinflammation in a mouse model of AD.
Main Methods:
- Biochemical assays including thioflavin T fluorescence, circular dichroism, and negative-stain electron microscopy to assess Aβ fibril formation.
- Nuclear magnetic resonance (NMR) spectroscopy for structural analysis of MDK's interaction with Aβ peptides.
- Proteomic analysis using mass spectrometry on whole proteome and detergent-insoluble fractions in 5xFAD Mdk knockout mice.
Main Results:
- MDK protein significantly attenuated the fibril formation of both Aβ40 and Aβ42 peptides in vitro.
- Mdk gene knockout in 5xFAD mice led to increased amyloid formation and heightened microglial activation in the brain.
- Mass spectrometry revealed significant accumulation of Aβ, Aβ-correlated proteins, and microglial components in Mdk-deficient 5xFAD mice.
Conclusions:
- Midkine (MDK) plays a protective role by counteracting amyloid pathology in Alzheimer disease (AD).
- MDK directly inhibits amyloid-beta (Aβ) assembly and fibril formation.
- MDK deficiency exacerbates AD-related amyloidosis and neuroinflammation, highlighting its therapeutic potential.
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