Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide
Chohan MO, Li B, Blanchard J, Tung YC, Heaney AT, Rabe A, Iqbal K, Grundke-Iqbal I. Neurobiol Aging. 2011 Aug;32(8):1420–1434. View source ↗
This paper reports the design and initial in vivo characterization of the 11-mer synthetic peptide "Peptide 6," derived from a biologically active region of ciliary neurotrophic factor (CNTF). In adult C57BL/6 mice, peripherally administered Peptide 6 induced proliferation of neural progenitor cells and increased survival and maturation of newly-born neurons in the dentate gyrus, as quantified by BrdU incorporation and double-labeling for neuronal markers. The peptide also increased MAP2 and synaptophysin immunoreactivity in the dentate gyrus, consistent with enhanced dendritic and synaptic markers. A 30-day subcutaneous slow-release implant produced improved reference memory in the Morris water maze. The authors reported a plasma half-life of approximately 6 hours and described the peptide as blood-brain-barrier permeable, with a proposed mechanism of competitive inhibition of leukemia inhibitory factor (LIF) signaling. This is the foundational publication on the Peptide 6 / P21 lineage and was conducted by the originating research group at the New York State Institute for Basic Research in Developmental Disabilities.
Researchers wanted a small synthetic peptide that could copy part of what a natural growth factor for neurons (CNTF) does, but be small enough to cross from the bloodstream into the brain. They designed an 11-amino-acid peptide they called "Peptide 6" based on a piece of CNTF. When normal adult mice received the peptide under the skin for thirty days using a slow-release implant, the researchers observed more new neurons being born and surviving in a memory-related part of the brain called the dentate gyrus. The mice also performed better on a standard rodent memory test (the Morris water maze). The peptide stayed in the blood for about six hours and appeared to act by blocking a signal called LIF that normally slows neurogenesis. This is the founding study that defined the Peptide 6 / P21 family — it was carried out by the same lab that originally designed the molecule.
