Molecular mechanism of neuronal cell death in Alzheimer's disease

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The selective neuronal degeneration in Alzheimer's disease (AD) has not been extensively studied, mainly due to few specific histological or molecular markers for neuronal subpopulations. Moreover, the intracellular signaling pathway involved in the neuronal degeneration remains to be analyzed. JNK3, a member of mitogen-activated protein kinase, expresses in a subset of neurons of the human nervous system. The distribution of these neurons closely matches that of AD targeted neurons. As a first step to clarify the JNK3 cascade, we have carried out yeast two-hybrid system to isolate cDNA clones of JNK3-binding proteins. One of the JNK3-binding proteins (termed BP#2) expresses exclusively in brain as JNK3. BP#2 can be a sustrate of JNK3, and the phosphorylated BP#2 no longer binds with the activated JNK3. Furthermore, we have found that BP#2 associates with not only JNK3 but also SEK1, an activator of JNK3. These results suggest that BP#2 works as a scaffold protein in the JNK3 cascade. The JNK3/BP#2 complex would dissociate through the phosphorylation of BP#2 done by JNK3.