Effects of Alzheimerʹs peptide and α1-antichymotrypsin on astrocyte gene expression

We employed gene array technology to investigate the effects of α1-antichymotrypsin (ACT), soluble or fibrillar Alzheimerʹs peptide (Aβ1–42) alone and the combination of ACT/Aβ1–42 on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble Aβ1–42 combination, 195 (70.6%) were suppressed. The ACT/fibrillar Aβ1–42 combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble Aβ1–42, were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril Aβ1–42 increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar Aβ1–42 alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/Aβ1–42 alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar Aβ1–42 alone, suggesting that pathogenic effects of Aβ1–42 may occur as a consequence of its association with other proteins.