Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease.
The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and 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. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of beta-amyloid (Abeta(1-42)), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of Abeta(1-42) (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal Abeta(1-42) implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). 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 Abeta(1-42)-mediated neurodegeneration.
Afkhami-Goli
Amir
A
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Noorbakhsh
Farshid
F
Keller
Avril J
AJ
Vergnolle
Nathalie
N
Westaway
David
D
Jhamandas
Jack H
JH
Andrade-Gordon
Patricia
P
Hollenberg
Morley D
MD
Arab
Hosseinali
H
Dyck
Richard H
RH
Power
Christopher
C
D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D044464:Receptor, PAR-2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000235:genetics; D044067:Receptors, Lipoxin / Q000096:biosynthesis / Q000235:genetics
D016229:Amyloid beta-Peptides; C105101:FPR2 protein, human; D010446:Peptide Fragments; D044464:Receptor, PAR-2; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse