Paper Information

Title: 

PROTEINASE-ACTIVATED RECEPTOR-2 EXERTS PROTECTIVE AND PATHOGENIC CELL TYPE-SPECIFIC EFFECTS IN ALZHEIMER'S DISEASE

Type: SPEECH
Author(s): AFKHAMI GOLI A.,NOURBAKHSH FARSHID,AVRIL J.K.,VERGNOLLE N.,WESTAWAY D.,JHAMANDAS J.H.,PATRICIA A.G.,MORLEY D.H.,ARAB H.A.,DYCK R.H.,POWER CH.
 
 
 
Name of Seminar: IRANIAN CONGRESS OF PHYSIOLOGY AND PHARMACOLOGY
Type of Seminar:  CONGRESS
Sponsor:  PHYSIOLOGY AND PHARMACOLOGY SOCIETY, MASHHAD UNIVERSITY OF MEDICAL SCIENCE
Date:  2007Volume 18
 
 
Abstract: 

The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, which mediate both neuroprotective and neuropathogenic effects, although their effects in neurodegenerative diseases remain uncertain. Alzheimer's disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. Herein, we report suppression of PAR2 expression in neurons of brains from AD patients, while PAR2 expression was increased in proximate glial cells, together with upregulation of pro-inflammatory cytokines and chemokines. In vitro, glial PAR2 activation increased expression of formyl peptide receptor-2 (FPR2), a cognate receptor for Ab1-42, enhanced microglia-mediated pro-inflammatory responses resulting in neuronal death. Conversely, neuronal PAR2 activation protected neurons against the toxic effects of Aβ1-42, a key component of AD neuropathogenesis. PAR2 deficient mice, following hippocampal Ab1-42 implantation, exhibited less neuroinflammation, together with improved neurobehavioral and neuropathological outcomes. Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to Ab1-42-mediated neurodegeneration.

 
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