| First Author | Delarasse C | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 4 | Pages | 2596-606 |
| PubMed ID | 21081501 | Mgi Jnum | J:168499 |
| Mgi Id | MGI:4888456 | Doi | 10.1074/jbc.M110.200618 |
| Citation | Delarasse C, et al. (2011) The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J Biol Chem 286(4):2596-606 |
| abstractText | The amyloid precursor protein (APP) is cleaved by beta- and gamma-secretases to generate the beta-amyloid (Abeta) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) patient brains. Non-amyloidogenic processing of APP by alpha-secretases leads to proteolytic cleavage within the Abeta peptide sequence and shedding of the soluble APP ectodomain (sAPPalpha), which has been reported to be endowed with neuroprotective properties. In this work, we have shown that activation of the purinergic receptor P2X7 (P2X7R) stimulates sAPPalpha release from mouse neuroblastoma cells expressing human APP, from human neuroblastoma cells and from mouse primary astrocytes or neural progenitor cells. sAPPalpha shedding is inhibited by P2X7R antagonists or knockdown of P2X7R with specific small interfering RNA (siRNA) and is not observed in neural cells from P2X7R-deficient mice. P2X7R-dependent APP-cleavage is independent of extracellular calcium and strongly inhibited by hydroxamate-based metalloprotease inhibitors, TAPI-2 and GM6001. However, knockdown of a disintegrin and metalloproteinase-9 (ADAM9), ADAM10 and ADAM17 by specific siRNA, known to have alpha-secretase activity, does not block the P2X7R-dependent non-amyloidogenic pathway. Using several specific pharmacological inhibitors, we demonstrate that the mitogen-activated protein kinase modules Erk1/2 and JNK are involved in P2X7R-dependent alpha-secretase activity. Our study suggests that P2X7R, which is expressed in hippocampal neurons and glial cells, is a potential therapeutic target in AD. |
