A new approach for developing a new drugs for alzheimer's disease (AD) and that for diagnosis for AD

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The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the presenilin2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease (AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a (HMGA1a) protein. HMGA1a bound to a specific sequence on exon 5, located upstream of the 5' splice site. HMGA1a expression was induced by hypoxia and the protein was accumulated in the nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated PS2V, but PS2V was repressed by cotransfection with the U1 snRNP 70K protein that has a strong affinity to HMGA1a. HMGA1a could interfere with U1 snRNP binding to the 5' splice site and caused exon 5 skipping. Inhibition of the binding of HMGA1a to PS2exon 5 inhibited the neuronal death caused by ER (endoplasmi reticulum) stress … More , suggesting the possibility to develop a new drug for AD. Furthermore, HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients.In addition, we found that human cappase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of A β and A β-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus is involved in pathogenesis of AD, and inhibition of caspase-4 may leads to develop a new drug for AD.We also found the high level of PS2V in cerebrospinal fluid of sporadic AD comparing with that of control, showing that alteration of PS2V level is useful for diagnosis of sporadic AD Less