RGD Reference Report - In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3beta and secretases. - Rat Genome Database

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In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3beta and secretases.

Authors: Diaz-Hernandez, JI  Gomez-Villafuertes, R  Leon-Otegui, M  Hontecillas-Prieto, L  Del Puerto, A  Trejo, JL  Lucas, JJ  Garrido, JJ  Gualix, J  Miras-Portugal, MT  Diaz-Hernandez, M 
Citation: Diaz-Hernandez JI, etal., Neurobiol Aging. 2012 Aug;33(8):1816-28. doi: 10.1016/j.neurobiolaging.2011.09.040. Epub 2011 Nov 1.
RGD ID: 10045669
Pubmed: PMID:22048123   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neurobiolaging.2011.09.040   (Journal Full-text)

beta-Amyloid (Abeta) peptide production from amyloid precursor protein (APP) is essential in the formation of the beta-amyloid plaques characteristic of Alzheimer's disease. However, the extracellular signals that maintain the balance between nonpathogenic and pathologic forms of APP processing, mediated by alpha-secretase and beta-secretase respectively, remain poorly understood. In the present work, we describe regulation of the processing of APP via the adenosine triphosphate (ATP) receptor P2X7R. In 2 different cellular lines, the inhibition of either native or overexpressed P2X7R increased alpha-secretase activity through inhibition of glycogen synthase kinase 3 (GSK-3). In vivo inhibition of the P2X7R in J20 mice, transgenic for mutant human APP, induced a significant decrease in the number of hippocampal amyloid plaques. This reduction correlated with a decrease in glycogen synthase kinase 3 activity in J20 mice, increasing the proteolytic processing of APP through an increase in alpha-secretase activity. The in vivo findings presented here demonstrate for the first time the therapeutic potential of P2X7R antagonism in the treatment of familiar Alzheimer's disease (FAD).

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease treatmentISOGsk3b (Mus musculus)10045669; 10045669protein:decreased phosphorylation:hippocampus:RGD 
Alzheimer's disease treatmentIEP 10045669protein:decreased phosphorylation:hippocampus:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gsk3b  (glycogen synthase kinase 3 beta)

Genes (Mus musculus)
Gsk3b  (glycogen synthase kinase 3 beta)

Genes (Homo sapiens)
GSK3B  (glycogen synthase kinase 3 beta)


Additional Information