HUMAN AMYLIN INDUCES APOPTOTIC PATTERN OF GENE-EXPRESSION CONCOMITANTWITH CORTICAL NEURONAL APOPTOSIS

Amylin forms large beta-pleated neurotoxic oligomers but shows only 38 % sequence similarity to A beta. As patterns of gene expression during neuronal apoptosis appear stimulus and cell type specific, we compare d the pattern of amylin-induced gene expression in rat cortical neuron s with that shown previously to be induced by A beta in order to evalu ate whether these two peptides with different primary but similar seco ndary structure induce apoptosis similarly, Morphologic and quantitati ve measures of cell death show widespread apoptotic death after amylin treatment. Amylin treatment results in time- and concentration-depend ent inductions of oxidative stress genes, such as cox-2 and I kappa B- alpha. ''Apoptotic'' genes are also induced in a time- and concentrati on-dependent manner, including c-jun, junB, c-fos, and fosB, followed temporally by a gene known to be modulated by these transcription fact ors, i.e., transin. In situ hybridization analyses show that c-fos exp ression is restricted largely to neurons with condensed chromatin, a h allmark of apoptosis. As these genes are not induced in ail models of apoptosis, that amylin-induced neuronal death is genetically similar t o that of A beta suggests that these peptides may be neurotoxic throug h a common mechanism.