Amyloid-β42 Drives Collagen-Independent Activation of Discoidin Domain Receptor 2 in Alzheimer’s Disease

Discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase (RTK) family member, plays a pivotal role in collagen-mediated signaling, influencing several key cellular processes. In Alzheimer’s disease (AD), DDR2 expression and activity are significantly upregulated. While collagens, the endogenous ligands of DDR2, either remain unchanged or are downregulated in AD-like conditions, Amyloid-beta 42 (Aβ42) has been found to activate DDR2 noncanonically in the absence of collagen. Additionally, DDR2 naturally translocates to the nucleus in the neuroblastoma cell line SH-SY5Y, and the nuclear pool of DDR2 further increases in the presence of Aβ42, suggesting a novel pathological role for DDR2 in AD. The E113K mutant of DDR2, where the collagen-binding site has been compromised, fails to get activated by collagen, whereas Aβ42 could still activate it. Furthermore, the DDR2 inhibitor WRG-28 effectively inhibits Aβ42 induced phosphorylation of the protein. We have modeled the ectodomain of DDR2 in silico, extending it through the transmembrane helix and subsequently docked the Aβ42 pentamer to provide a structural hypothesis for elucidating the mechanistic basis of Aβ-mediated kinase activation. Additionally, we analyzed WRG-28 binding by forming a ternary complex among DDR2, Aβ42, and WRG-28. Our structural analyses offer key insights into the molecular mechanisms governing DDR2 activation by Aβ42 and its inhibition by WRG-28 in the AD cell model, providing a foundation for targeted therapeutic strategies.