Neuronal cell death is a pathological hallmark of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and prion protein diseases (PrP). Therapy directed at eliminating the primary neurotoxic event that leads to cell death may be very effective against neurodegenerative diseases.

Several studies in the literature have now shown that an endogenously produced peptide, Humanin, can abolish cell death in neuronal cells. Humanin is a 24 amino acid secreted peptide encoded by both nuclear and mitochondrial genomes. (PNAS, 98:6336-6341, 2001, J Neurosci, 21:9235-9245, 2001, Neuroscience Letters, 324:227-231, 2002). Humanin has been shown to rescue cortical neurons from PrP118-135 fragment induced apoptosis (Mol Cell Neurosci, 25:95-102, 2004). Humanin also protected neurons from the neurotoxic effects of beta amyloid 1-42 and beta amyloid 25-35 (J Neurosci, 21:9235-9245, 2001).

Additional studies on various derivatives of Humanin reveal that replacing serine at position 14 with a glycine residue produced a peptide that was 500 to 1000 fold more potent than Humanin. Humanin S14G prevented the beta amyloid 25-35 induced impairment of short term memory in mice (Mol Cell Neurosci, 25:95-102, 2004, J Neurosci Res, 79: 714-723, 2004). Combining a 17 amino acid derivative of Humanin with the activity-dependent neurotrophic factor (ADNF) resulted in a derivative of Humanin, named Colivelin,that was 1000 fold more potent. Both Humanin and Colivelin are effective against mouse dementia and neuronal death induced by injection of beta amyloid. Colivelin also has been shown to be as effective as VEGF and IGF-1 in prolonging survival of ALS mice. Colivelin improves both motor performance and survival of ALS mice (J Neurosci, 25:10252-10261, 2005, BBRC, 343:793-798, 2006, CNS Drug Reviews, 12:113-122, 2006, Mol Neurobiol, 35:55-84, 2007).

Humanin has been shown to suppress apoptosis by interfering with Bax activation. Humanin prevents the translocation of Bax from the cytosol to the mitochondria. Humanin also binds BimEL and Bid and inhibits their induced release of SMAC and cytochrome c from mitochondria. Addition of a membrane penetrating polyarginine sequence to Humanin resulted in suppressed caspase activation in HEK293T cells (Nature, 423:456-461, 2003, J Biol Chem, 280:15825-15835, 2005, J Biol Chem, 280:15815-15824, 2005).

Humanin is a secreted peptide and may function through a cell surface receptor. Both beta amyloid 1-42 and prion peptide PrP 106-126 interact with the formyl peptide receptor-like 1 (FPRL 1)(Cytokine and Growth Factor Reviews, 12:91-105, 2001, International Immunopharmacology, 2:1-13, 2002). Studies now show that Humanin acts as a ligand for FPRL 1 and shares the receptor with beta amyloid and PrP106-126. The blocking of beta amyloid and PrP106-126 by Humanin to the cell surface receptor FPRL 1 may be a mechanism by which Humanin suppresses neuronal death (J Immunology, 172:7078-7085, 2004). The discovery that Humanin binds to FPRL 1 suggested that the N-formyl derivative of Humanin would be more potent than Humanin. A recent study has shown that N-Formylated Humanin was more potent as a ligand for FPRL 1 than Humanin (BBRC, 324:255-261, 2004).