Hematopoietic prostaglandin D synthase and DP1 receptor are selectively upregulated in microglia and astrocytes within senile plaques from human patients and in a mouse model of Alzheimer disease.
Prostaglandin (PG) D2 is produced in activated microglia by the action of hematopoietic PGD synthase (HPGDS) and plays important roles in neuroinflammation. Because the fact that neuroinflammation accelerates progression of Alzheimer disease (AD) has been documented, we investigated whether PGD2 is also involved in the pathology of AD. Here, we report that the level of the mRNA of the receptor for PGD2 (DP1) was increased in AD brains compared with the level in non-AD brains. Immunocytochemical analysis showed HPGDS expression to be localized in the microglia surrounding senile plaques. In situ hybridization studies revealed that DP1 mRNA was specifically localized in microglia and reactive astrocytes within senile plaques of AD brains. In the brain of Tg2576 mice, a model of AD, HPGDS and DP1 proteins were mainly localized immunocytochemically in microglia and astrocytes in the plaques, and the levels of their mRNAs increased in parallel with amyloid beta deposition. These results indicate that PGD2 may act as a mediator of plaque-associated inflammation in AD brain and may explain the pharmacologic mechanisms underlying the favorable response of patients with AD to nonsteroidal anti-inflammatory drugs.
Mohri
Ikuko
I
FrDepartment of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kadoyama
Keiichi
K
Kanekiyo
Takahisa
T
Sato
Yo
Y
Kagitani-Shimono
Kuriko
K
Saito
Yuko
Y
Suzuki
Kinuko
K
Kudo
Takashi
T
Takeda
Masatoshi
M
Urade
Yoshihiro
Y
Murayama
Shigeo
S
Taniike
Masako
M
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D054834:Lipocalins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C036293:prostaglandin D2 receptor