Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor.
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 (Abeta(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 Abeta(42), AD brain tissue also generates protective factor(s) that may antagonize the neurodestructive effect of Abeta(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 Abeta(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 Abeta(42) to chemoattract and activate phagocytic cells. Humanin reduced the aggregation and fibrillary formation by suppressing the effect of Abeta(42) on mononuclear phagocytes. In neuroblast cells, Humanin and Abeta(42) both activated FPRL1; however, only Abeta(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 Abeta(42) and suggest that Humanin may exert its neuroprotective effects by competitively inhibiting the access of FPRL1 to Abeta(42).
Ying
Guoguang
G
Laboratory of Molecular Immunoregulation and. Basic Research Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Iribarren
Pablo
P
Zhou
Ye
Y
Gong
Wanghua
W
Zhang
Ning
N
Yu
Zu-Xi
ZX
Le
Yingying
Y
Cui
Youhong
Y
Wang
Ji Ming
JM
D000544:Alzheimer Disease / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000819:agonists / Q000187:drug effects*
D016229:Amyloid beta-Peptides; C105101:FPR2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011506:Proteins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; C427211:humanin