Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Masihuz Zaman; Shu Yang; Ya Huang; Jay M. Yarbro; Yanhong Hao; Zhen Wang; Danting Liu; Kiara E. Harper; Hadeer Soliman; Alex Hemphill; Sarah Harvey; Shondra M. Pruett‐Miller; Valerie Stewart; Ajay Singh Tanwar; Ravi Kalathur; Christy R. Grace; Martin Turk; Sagar Chittori; Yun Jiao; Zhiping Wu; Anthony A. High; Xusheng Wang; Geidy E. Serrano; Thomas G. Beach; Gang Yu; Yang Yang; Ping‐Chung Chen; Junmin Peng

doi:10.1101/2025.03.20.644383

BiochemistrybioRxivMar 20, 2025

Preprint

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Masihuz Zaman iD, Shu Yang iD, Ya Huang iD, Jay M. Yarbro iD, Yanhong Hao iD, Zhen Wang iD, Danting Liu iD, Kiara E. Harper, Hadeer Soliman, Alex Hemphill, Sarah Harvey, Shondra M. Pruett‐Miller iD, Valerie Stewart, Ajay Singh Tanwar iD, Ravi Kalathur iD, Christy R. Grace iD, Martin Turk iD, Sagar Chittori iD, Yun Jiao iD, Zhiping Wu iD, Anthony A. High iD, Xusheng Wang iD, Geidy E. Serrano iD, Thomas G. Beach iD, Gang Yu iD, , Junmin Peng iD

Abstract

Proteomic profiling of Alzheimers disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with A{beta} since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates A{beta} assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both A{beta}40 and A{beta}42 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 A{beta} and A{beta}-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimers disease.

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