Opposite effects of P2X7 and P2Y2 nucleotide receptors on α-secretase-dependent APP processing in Neuro-2a cells

The amyloid precursor protein (APP) is proteolytically processed by beta- and gamma-secretases to release amyloid-beta peptide (Ab), the main component found in senile plaques of Alzheimer's disease (AD) patient brains. Alternatively, APP can be cleaved within the A beta sequence by alpha-secretase, thus precluding the generation of A beta. We have demonstrated that activation of the P2X7 receptor leads to a reduction of alpha-secretase activity in Neuro-2a cells. Moreover, the P2X7 ligand 2'(3')-O-(4-benzoylbenzoyl) ATP (BzATP) can also activate a different P2 receptor in these cells. This receptor, whose pharmacology resembles that of the P2Y(2) receptor, has an opposite effect, leading to increases in alpha-secretase activity. Our study suggests that P2X7R and P2Y(2)R could be novel therapeutic targets in AD. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.