| Research Abstract |
In this research term, we found and reported that the mechanism of Humanin (HN) neuroprotective activity against Alzheimer's disease (AD)-relevant indults and the novel AD-relevant neuronal cell death mechanisms, especially we found the natural and neuronal cell death inducible ligand for amyloid precursor protein (APP).
1.The mechanisms of HN neuroprotection
In 2001, we found HN which is consisted of 24 amino acids, and inhibited neuronal cell death by AD-relevant insults such as familial AD (FAD)-linked APP mutants, presenilin-1 (PS1) mutants, PS2 mutants, neurotoxic amyloid-β peptides. It is not fully understood the HN neuroprotective functions. We succeeded HN-derivatives which have no neuroprotective activity but have its self-dimerization activity. So, these derivatives (P3A, L12A, S14A, and P19A) can act as HN antagonists.
Until now, genetistein, a typical tyrosine kinase inhibitor, inhibited HN activity against V642I-APP-induced F11 neurohybrid cell death. Therefore, we used vario
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us kinase inhibitors and mutant genes which can act as dominant negative forms. We identified the involvement of signal transducer and transcription 3 (STAT3) in HN neuroprotective activity against AD-relevant insults induced neuronal cell death. These indicated that the putative receptor complex for HN is upstreams of STAT3 and related to certain tyrosine kinases. These results are important for the identification of HN receptor complex and small compound which can mimic HN action.
2.The molecular mechanisms of AD-relevant neuronal cell death
Until now, we found and reported that 22C11, a monoclonal antibody developed against extracellular domain of APP, can induce neuronal cell death. In addition, we reported that pertussis toxin (PTX) sensitive Go protein, Gβγ proteins, c-Jun N-terminal kinase, NADPH oxidase, and caspase-3/related caspase are involved in the neuronal cell death. By various binding experiments and cell death experiments, we found that transforming growth factor β2 (TGFβ2) binds to the extracellular domain of APP and induce the neuronal cell death via APP in PTX sensitive manner. In addition, we reported that the protein expression of TGFβ2 in cortex M1 region of 18-months-old female Tg2576 Alzheimer's disease model mouse. From these results, there is a possibility that TGFb2 is involved in the onset of AD.
The p75 neurotrophin receptor (p75NTR) is a candidate for Aβ receptor which can cause neuronal cell death. In 2002, PLAIDD molecule has been identified by Frankowski et al., and is similar to p75NTR. Therefore, we attempted to investigated the involvement of PLAIDD in Aβ/p75NTR-induced neuronal cell death. From the results, we concluded that PTX sensitive Gi proteins bind to the intracellular domain of PLAIDD and Aβ/p75NTR/PLAIDD can trigger the neuronal cell death as same as Aβ/p75NTR. Less
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