In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3ß and secretases.
Neurobiol Aging
; 33(8): 1816-28, 2012 Aug.
Article
in En
| MEDLINE
| ID: mdl-22048123
ABSTRACT
ß-Amyloid (Aß) peptide production from amyloid precursor protein (APP) is essential in the formation of the ß-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 α-secretase and ß-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 α-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 α-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).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Plaque, Amyloid
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Glycogen Synthase Kinase 3
/
Amyloid Precursor Protein Secretases
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Receptors, Purinergic P2X7
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Purinergic P2X Receptor Antagonists
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Alzheimer Disease
Limits:
Animals
/
Humans
Language:
En
Journal:
Neurobiol Aging
Year:
2012
Document type:
Article
Affiliation country:
España