PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.
Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared with wild type mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. β-amyloid-induced toxicity (18.0 ± 7.1%) and Ca(2+) response (91.8 ± 12.9%) were also reduced in EP1(-/-) neurons compared with control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with cyclooxygenase-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Gehua
G
Zhen
Yun Tai
YT
Kim
Rung-chi
RC
Li
Jennifer
J
Yocum
Nidhi
N
Kapoor
John
J
Langer
Peter
P
Dobrowolski
Takayuki
T
Maruyama
Shuh
S
Narumiya
Sylvain
S
Doré
D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D002545:Brain Ischemia / Q000150:complications*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000150:complications* / Q000209:etiology; D010077:Oxazepines / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1 / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006834:Hydrazines; D010077:Oxazepines; C508853:PSEN1 protein, human; C545635:PTGER1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D058306:Receptors, Prostaglandin E, EP1 Subtype; C075222:amyloid beta-protein (1-42); C086836:SC 51089; D005947:Glucose; D002118:Calcium