Detailed characterization of Humanin, a newly identified anti-Alzheimer's disease peptide and potential starting point for development of the first curative therapy for Alzheimer's disease

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No fundamental therapy for Alzheimer's disease (AD) has so far been developed. Humanin is a newly identified peptide that suppresses cell death by Alzheimer's disease (AD)-related insults. We have investigated the structure/function relationship for the neuroprotective function of HN peptide. When either Pro3, Ser7, Cys8, Leu9, Leu 12, Thr13, Ser14, or Pro19 is changed to Ala in full-length HN, the HN derivatives lose its neuroprotective activity. Pro3-Pro19 turned out to be the core domain for neuroprotection by HN. HN forms a homodimer, which is essential for HN neuroprotection, and that Ala substitution for Ser7 or Leu9 nullifies homodimerization by HN. HN should be secreted and be able to act from the outside, indicating that a certain cell-surface receptor is the target of HN. HN immunoreactivity is detected in some of the intact large neurons in the occipital lobe of an AD brain, but not in other brain regions or in an age-matched control brain. In mice, 3 kDa immunoreactive pept … More ide, the deduced molecular weight of HN, has been detected in the testes and colons of 3-week-old mice. This immunoreactivity disappears in the colon of 12-week-old mice, pointing to the age-dependent regulation of HN production. We identified TRIM11 as a HN-interacting protein, a member of a protein family containing a tripartite motif (TRIM). TRIM11 is composed of a RING finger domain, which is a putative E3 ubiquitin ligase. Notably, TRIM11 ubiquitinizes and degrades HN intracellularly. We also found that the potentiation of HN neuroprotective function by Gly substitution for Ser14 is specifically mimicked by D-Ser isomerization. Therefore, it is conceivable that HN peptide is transcribed and translated from the HN gene and then converted to the maximally active form by posttranslational modification at Ser14, that is, D-Ser14 isomerization. Considering that insulin-like growth factor-binding protein 3 is an HN-binding protein in the blood [20], it is an attractive hypothesis that HN is mainly produced in tissues outside the central nervous system (CNS), transferred by binding to the binding protein, and further activated as it passes through the blood-brain barrier, and is delivered to CNS neurons. Considering the broad specificity of its rescue activity to AD-relevant insults, HN is a promising seed for AD therapy aiming the complete suppression of neuronal loss. Less