Search for the proteins linked to Alzheimer's disease-specific neuronal death and application for the therapeutics.

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Intracellular amyloid-β (Aβ) 42, the major constituent of the senile plaques in the Alzheimer's disease (AD) brain, may be even more important in the AD-related neuronal death than extracellular Aβ42. Previously, we have reported that intracellular Aβ42 contributes to the p53-dependent neuronal death. To further understand the mechanism of AD-specific neuronal death, we are searching for the novel proteins related to that mechanism. Recently, we have established a fine differential display system of intracellular proteins using 2-demensional electrophoresis (2DE). Presenilin (PS) 1 and 2 are the major causes of early-onset familial AD, and the mutations in PS1/2 are deeply associated with the AD-specific neuronal death. Also, extrinsic stress such as oxidative stress may trigger the neuronal death in AD. Thus, we compared the protein profiles in the mutant PS1/2- and wild-type PS1/2-transfected SH-SY5Y cells in the normal condition or stressed condition, e.g. deprivation of serum in the medium. In this case, appearing (increasing) or disappearing (decreasing) protein spots in the stressed mutant PS1/2-transfected cells may be importantly associated with the process of PS1/2 mutation-related cell death. We have selected some candidate spots out of total 500-2000 spots, and attempting to identify these proteins using mass-spectrometry system. Those proteins would be associated with cell cycle, ER stress, ubiquitin-proteasome, signal transduction, or unknown other systems. Thus, 2DE-differential display is a unique tool for searching for disease-related proteins, and may contribute to development of the cure of AD-related neurodegeneration.