id_690. A MATRIX-DERIVED PEPTIDE THAT CALMS BRAIN IMMUNE CELLS: EXPLORING GLYCINE–HISTIDINE–LYSINE-COPPER (GHK-CU) AS A REGULATOR OF MICROGLIAL FUNCTIONS
Mitchell Beckedorf1, Tyler J. Wenzel2, Andis Klegeris1
1 Faculty of Science, University of British Columbia Okanagan Campus, 3187 University Way , Kelowna, BC, V1V 1V7, Canada
2 College of Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada
INTRODUCTION: Alzheimer’s disease (AD) is the leading cause of dementia worldwide and is characterized by amyloid-β and tau accumulation with chronic neuroinflammation. As the resident immune cells of the central nervous system (CNS), microglia play a key role in disease progression and are important therapeutic targets. Matrikines are bioactive peptides released from the extracellular matrix during tissue remodeling that regulate immune signaling and homeostasis across multiple tissues and have been studied mainly in the periphery. Emerging evidence indicates that matrikines are also released in the CNS, where they contribute to homeostasis and neuroimmune regulation. The copper-binding tripeptide glycine–histidine–lysine (GHK) is a matrikine with established anti-inflammatory and regenerative actions in the periphery, yet its effects in the brain remain poorly understood.
AIM(S): To evaluate the effects of GHK and its copper complex, GHK-Cu, on microglia-like cells under oxidative stress and neuroinflammation relevant to AD.
METHOD(S): BV-2 murine microglial cells and differentiated HL-60 human promyelocytic cells were treated with GHK, GHK-Cu, or CuSO₄ prior to stimulation with lipopolysaccharide or interferon-γ. Inflammatory mediators, nitric oxide, and reactive oxygen species were quantified. Phagocytosis and morphological changes were assessed by fluorescence microscopy.
RESULTS: GHK-Cu reduced IL-6 and nitric oxide in activated BV-2 microglia and suppressed reactive oxygen species in primed HL-60 cells. It increased phagocytic activity and decreased cell circularity, indicating reduced reactive morphology. Copper-free GHK had no effect, while CuSO₄ induced cytotoxicity. GHK-Cu protected microglia from inflammatory toxicity but did not significantly reduce their neurotoxicity.
CONCLUSIONS: GHK activity in the CNS depends on copper complexation. By suppressing pro-inflammatory signaling and enhancing phagocytosis, GHK-Cu may restore microglial homeostasis and is a promising endogenous modulator of neuroinflammation.
FINANCIAL SUPPORT: NSERC Canada; J. Brown and Family Alzheimer’s Disease Research Foundation.