Certain cases of familial Alzheimer's disease are caused by mutants of amyloid-β precursor protein (AβPP), including V642I-AβPP, K595N/M596L-AβPP (NL-AβPP), A617G-AβPP, and L648P-AβPP. By using an unbiased functional screening with transfection and expression of a human brain cDNA library, we searched for genes that protect neuronal cells from toxicity by V642I-AβPP. One protective clone was identical to the human GTX, a neuronal homeobox gene. Human Gtx (hGtx) inhibited caspase inhibitor-sensitive neuronal cell death not only by V642I-AβPP but also by L648P-, NL-, A617G-AβPP, apolipoprotein E4, and Aβ. The region of hGtx responsible for this rescue function was specified to be its homeodomain (Lys148-His207). The rescue function was shared by DLX4, a distal-less family gene with a homeodomain only 38.3% homologous to that of hGtx, suggesting that this function would be generally shared by homeodomains. The neuroprotective function of hGtx was attributable to hGtx-stimulated production and secretion of insulin-like growth factor-I. This study provides molecular clues to understand how neuronal cells developmentally regulate themselves against cell death as well as to develop reagents effective in curative therapeutics of Alzheimer's disease.
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