Deposition of
amyloid-beta (Aβ)
protein, a 39-43
amino acid peptide, in the brain is a major pathological feature of
Alzheimer's disease (AD). We have previously provided evidence that in primary cultures of rat basal forebrain and human fetal neurons (HFNs), neurotoxic effects of oligomeric Aβ are expressed through the
amylin receptor. In this study, we utilized RT-PCR arrays to compare
RNA expression levels of 84 markers for pro and anti- apoptotic signalling pathways following exposure of HFNs to either Aβ(1-42) (20 μM) or human
amylin (2 μM). Oligomeric Aβ(1-42) or human
amylin was applied to HFNs alone or after pre-treatment of cultures with the
amylin receptor antagonist, AC253. Changes in
RNA levels were then quantified and compared to each other in order to identify increases or decreases in gene expression of apoptotic markers. Applications of Aβ(1-42) or human
amylin, but not the inactive inverse sequence Aβ(42-1) or rat
amylin, resulted in a time-dependent marked increase in mediators of apoptosis including
a 10- to 30-fold elevations in
caspases 3, 6, 9, BID and XIAP levels.
Amylin receptor antagonists, AC253 (10 μM) or
AC187 (10 μM), significantly attenuated the induction of several pro-apoptotic mediators up-regulated following exposure to Aβ(1-42) or human
amylin and increased the expression of several anti-apoptotic markers. These data allow us to identify key elements in the Aβ-induced apoptosis that are blocked by antagonism of the
amylin receptor and further support the potential for
amylin receptor blockade as a potential therapeutic avenue in AD.