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The Journal of Immunology, 2004, 172: 7078-7085.
Copyright © 2004 by The American Association of Immunologists

Humanin, a Newly Identified Neuroprotective Factor, Uses the G Protein-Coupled Formylpeptide Receptor-Like-1 as a Functional Receptor1

Guoguang Ying*, Pablo Iribarren*, Ye Zhou*, Wanghua Gong{dagger}, Ning Zhang*, Zu-Xi Yu{ddagger}, Yingying Le*, Youhong Cui* and Ji Ming Wang2,*

* Laboratory of Molecular Immunoregulation and {dagger} Basic Research Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and {ddagger} Pathology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Alzheimer’s disease (AD) is characterized by overproduction of {beta} amyloid peptides in the brain with progressive loss of neuronal cells. The 42-aa form of the {beta} amyloid peptide (A{beta}42) is implied as a major causative factor, because it is toxic to neurons and elicits inflammatory responses in the brain by activating microglial cells. Despite the overproduction of A{beta}42, AD brain tissue also generates protective factor(s) that may antagonize the neurodestructive effect of A{beta}42. Humanin is a gene cloned from an apparently normal region of an AD brain and encodes a 24-aa peptide. Both secreted and synthetic Humanin peptides protect neuronal cells from damage by A{beta}42, and the effect of Humanin may involve putative cellular receptor(s). To elucidate the molecular identity of such receptor(s), we examined the activity of synthetic Humanin on various cells and found that Humanin induced chemotaxis of mononuclear phagocytes by using a human G protein-coupled formylpeptide receptor-like-1 (FPRL1) and its murine counterpart FPR2. Coincidentally, FPRL1 and FPR2 are also functional receptors used by A{beta}42 to chemoattract and activate phagocytic cells. Humanin reduced the aggregation and fibrillary formation by suppressing the effect of A{beta}42 on mononuclear phagocytes. In neuroblast cells, Humanin and A{beta}42 both activated FPRL1; however, only A{beta}42 caused apoptotic death of the cells, and its cytopathic effect was blocked by Humanin. We conclude that Humanin shares human FPRL1 and mouse FPR2 with A{beta}42 and suggest that Humanin may exert its neuroprotective effects by competitively inhibiting the access of FPRL1 to A{beta}42.


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