Search for neuronal cell death-inhibiting drugs for Alzheimer's disease-relevant signal transduction

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In this research program, we have examined the neuronal cell death mechanism underlysing Alzhemer’s disease (AD), and identified an antagonist of Humanin (HN) which inhibited AD-relevant neuronal cell death and an endogenous agonist of HN receoptor complex composed of WSX-1, ciliary neurotrophic factor receptor/gp130. The results were: (1) MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal, (2) V-set transmembrane domain containing 2 like inhibited HN’s activity via direct binding, and (3) A series of experiments also showed that calmodulin-like skin protein (CLSP), highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. CLSP inhibited familial AD-linked V642I-APP-induced neuronal cell death via its binding to HN receptor following activation of JAK2/STAT3 axisThese results suggest that CLSP play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.