title: Role of P2X7 and P2Y2 receptors on α-secretase-dependent APP processing: Control of amyloid plaques formation "in vivo" by P2X7 receptor.
abstract: Amyloid precursor protein (APP) is expressed in a large variety of neural and non-neural cells. The balance between non-pathogenic and pathologic forms of APP processing, mediated by α-secretase and β-secretase respectively, remains a crucial step to understand β-amyloid, Aβ42 peptide, formation and aggregation that are at the origin of the senile plaques in the brain, a characteristic hallmark of Alzheimer's disease (AD). In Neuro-2a, a neuroblastoma cell line that constitutively expresses APP, activation of the P2X7 receptor leads to reduction of α-secretase activity, the opposite effect being obtained by P2Y2 receptor activation. The in vivo approach was made possible by the use of J20 mice, a transgenic mouse model of familial Alzheimer's disease (FAD) expressing human APP mutant protein. This animal exhibits prominent amyloid plaques by six months of age. In vivo inhibition of the P2X7 receptor induced a significant decrease in the number and size of hippocampal amyloid plaques. This reduction is mediated by an increase in the proteolytic processing of APP through α-secretase activity, which correlates with an increase in the phosphorylated form of GSK-3, a less active form of this enzyme. The in vivo findings corroborate the therapeutic potential of P2X7 antagonists in the treatment of FAD.
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Diaz-Hernandez
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gomez-Villafuertes
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Diaz-Hernandez
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Artalejo
authors.affiliation: Biochemistry Department, School of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain, Institute of Neurochemistry (IUIN), Complutense University of Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gualix
keywords: APP processing; Alzheimer's disease; GSK-3; P2X7 receptor; P2Y2 receptor; α-Secretase
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