Investigation of cellular and molecular targets in the brain of mice given intranasal GHK peptide to treat age-related cognitive decline

Abstract

There are currently 1.2 billion people worldwide over the age of 60 and this number is projected to double by 2050. With the world population over 60 reaching 22% within the next 50 years, there is an increasing need to understand the mechanisms and processes of aging. An area of major interest is brain aging given that approximately 2 out of 3 Americans experience some level of cognitive impairment by age 70. Neuropathology associated with this cognitive impairment can lead to more severe neuropathology associated with Alzheimer’s disease and other dementias providing a need to develop interventions to treat and potentially prevent or reverse age related cognitive decline. One particular therapeutic of interest is a naturally occurring peptide called glycyl-L-histidyl-L-lysine (GHK) as recent studies suggest that GHK in its Cu bound form has the potential to age related cognitive decline. In order to further investigate the potential of GHK-Cu as a therapeutic for age related cognitive decline, mouse hippocampal tissue from 20-month-old C57BL/6 mice treated with 15mg/kg of intranasal GHK-Cu daily for 8 weeks were used for immunohistochemistry and RNA sequencing to discover cellular and molecular targets of this peptide. Results suggested that mice treated with intranasal GHK-Cu had lower expression of potentially harmful astrocytes. RNA sequencing results revealed that mice treated with GHK-Cu had upregulation or downregulation of various gene pathways in a way that supports healthy brain aging. Sex differences were also observed with certain pathways being affected differently in males and females. These findings provide rationale for further investigation of GHK-Cu as a therapeutic for age related cognitive decline in preclinical and clinical studies.