Exploring the Neuroprotective Effects of GHK-Cu in-vitro with astrocyte C8-S and in-vivo with 5XFAD transgenic mice

Abstract

Astrocytes play a critical role in the progression of Alzheimer’s disease (AD), contributing to synaptic dysfunction, neurodegeneration, and altered neural homeostasis through reactive gliosis and phenotypic shifts. However, therapeutic strategies specifically targeting astrocyte dysfunction in AD remain underexplored. Glycyl-L-histidyl-L-lysine copper (GHK-Cu), an endogenous tripeptide with tissue-reparative properties, has recently emerged as a potential modulator of glial biology. This study investigated the efficacy of intranasally administered GHK-Cu in modulating astrocyte-driven neuroinflammation in the 5xFAD transgenic mouse model of AD and examined underlying mechanisms using an astrocyte cell line stimulated with lipopolysaccharide (LPS). Results revealed a significant sex-dependent reduction in hippocampal astrocytic activation, as indicated by decreased GFAP expression and reduced MCP-1 levels in GHK-Cu–treated female 5xFAD mice compared to untreated controls. Correspondingly, in vitro experiments using murine C8-S astrocytes demonstrated that GHK-Cu treatment, when applied either before or after lipopolysaccharide (LPS) exposure, mitigated astrocyte reactivity. These findings suggest that GHK-Cu modulates key features of astrocytic pathology in AD, including reactive transformation and stress-associated signaling. The data support further exploration of GHK-Cu as a therapeutic candidate targeting astrocyte dysfunction in neurodegenerative disease.