GHK-Cu Copper Peptide (100MG)

This study by Tucker et al. (University of Washington) was published in Aging Pathobiology and Therapeutics in 2024, after a 2023 preprint. It tested intranasal GHK-Cu in 5xFAD mice. These transgenic mice carry amyloid precursor protein and presenilin-1 mutations and develop amyloid plaques from about 3–4 months of age. Researchers use the model to study amyloid pathology and related behavioral changes.

Male and female 5xFAD mice received GHK-Cu or saline in the nose three times a week for 12 weeks, from 4 to 7 months of age. Researchers measured spontaneous alternation in a Y-maze, amyloid plaques and MCP-1, an inflammatory chemokine, in brain tissue.

Scope: This was a study in transgenic mice with small groups. It did not test GHK-Cu in people.

• Citation: Tucker M, Liao GY, Keely A, et al. Aging Pathobiol Ther. 2024;6(3):102–108.
• Animals: Male and female 5xFAD transgenic mice and wild-type littermates (C57BL/6J background), 4–7 animals per group
• Comparison: Intranasal saline
• Administration in the study: Intranasal drops under brief isoflurane anesthesia, three times per week for 12 weeks
• Measurements: Y-maze spontaneous alternation at weeks 4, 8 and 12; Congo red staining for amyloid plaques; MCP-1 immunohistochemistry
• Funding: National Institutes of Health

The authors cited earlier work linking GHK-Cu to tissue remodeling and antioxidant activity, a gene-profiling analysis (Connectivity Map) in which GHK-Cu counteracted impaired TGFβ1 signaling, and a prior study in aging mice. They wanted to know whether intranasal GHK-Cu would change the timing of behavioral and tissue changes in 5xFAD mice.

They chose intranasal delivery because it can reach the brain through olfactory and trigeminal pathways and partly bypass the blood–brain barrier. Their lab had previously tested this route in mice.

Transgenic and wild-type mice of both sexes were split into GHK-Cu and saline groups. GHK-Cu was given at 15 mg/kg body weight. The authors calculated that this contained about 2.1 mg/kg copper, below the 35 mg/kg level they cited for copper toxicity in mice. These amounts describe the published mouse protocol only.

Under light anesthesia, mice were tilted head-down, and 20 µL was applied drop by drop to alternating nostrils, timed with breathing. Dosing was three times weekly, which the authors chose to limit repeated anesthesia and possible irritation of the nasal lining.

Outcomes:

• Y-maze spontaneous alternation: A standard test of spatial working memory in rodents, run at weeks 4, 8 and 12
• Amyloid plaques: Congo red staining, counted across ten microscope fields
• MCP-1: Immunohistochemistry with digital quantification of staining intensity in the frontal cortex and hippocampus

Saline-treated 5xFAD mice showed lower spontaneous alternation than wild-type mice. Among female 5xFAD mice, the GHK-Cu group had higher alternation percentages than the saline group at weeks 8 and 12. Among males, the GHK-Cu group had higher alternation percentages from week 4 onward. In both sexes, GHK-Cu-treated transgenic mice reached alternation levels comparable to wild-type mice.

5xFAD mice of both sexes developed plaques in the midbrain and thalamus, frontal cortex and hippocampus. Wild-type littermates had no plaques. GHK-Cu-treated transgenic mice had significantly fewer detectable plaques than saline-treated transgenic mice, regardless of sex. On visual inspection, plaques in saline-treated mice tended to be larger and more densely stained.

MCP-1 is a chemokine that recruits immune cells and is often measured as a marker of inflammatory activity in brain tissue. In both sexes, 5xFAD mice given GHK-Cu showed lower MCP-1 staining intensity in the frontal cortex and hippocampus than saline-treated 5xFAD mice.

• Groups were small (4–7 mice per cohort), and the study lasted 12 weeks.
• Cognition was assessed with one behavioral test (Y-maze). Plaques and MCP-1 were measured by staining rather than biochemical quantification.
• The study did not measure GHK-Cu or copper levels in brain or blood, neuronal loss, or tau pathology.
• The authors stated that the safety of repeated intranasal GHK-Cu needs further assessment, including inflammation of the nasal lining.
• 5xFAD mice model aggressive, early amyloid pathology. Results in this model do not establish effects, safety or dosing in people.

In Tucker et al. (2024), 12 weeks of intranasal GHK-Cu in 5xFAD transgenic mice was associated with Y-maze alternation scores comparable to wild-type mice, fewer amyloid plaques and lower MCP-1 staining in the frontal cortex and hippocampus compared with saline-treated 5xFAD mice. The authors called for further studies in older animals, including measures of neuronal loss and nasal safety.

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