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.

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The promoter function of the rat lipocalin-type prostaglandin D synthase (L-PGDS) gene was characterized in primary cultures of leptomeningeal cells prepared from the neonatal rat brain. Luciferase reporter assays with deletion and site-directed mutation of the promoter region (؊1250 to ؉77) showed that an AP-2 element at ؊109 was required for activation and an E-box at ؉57, for repression. Binding of nuclear factors to each of these cis-elements was demonstrated by an electrophoretic mobility shift assay. Several components of the Notch-Hes signaling pathway, Jagged, Notch1, Notch3, and Hes-1, were expressed in the leptomeningeal cells. Human Hes-1 co-expressed in the leptomeningeal cells bound to the E-box of the rat L-PGDS gene, and repressed the promoter activity of the rat L-PGDS gene in a dose-dependent manner. The L-PGDS gene expression was up-regulated slowly by interleukin-1␤ to the maximum level at 24 h. The reporter assay with deletion and mutation revealed that two NF-B elements at ؊1106 and ؊291 were essential for this up-regulation. Binding of two NF-B subunits, p65 and c-Rel, to these two NF-B elements occurred after the interleukin-1␤ treatment. Therefore, the L-PGDS gene is the first gene identified as the target for the Notch-Hes signal through the E-box among a variety of genes involved in the prostanoid biosynthesis, classified to the lipocalin family, and expressed in the leptomeninges. Moreover, the L-PGDS gene is a unique gene that is activated slowly by the NF-B system. Lipocalin-type prostaglandin (PG)1 D synthase (L-PGDS) was first identified in the rat brain as an enzyme that catalyzes the conversion to PGD 2 from PGH 2 , the latter being a common precursor of all prostanoids (1). Later, L-PGDS was found to be identical to ␤-trace (2, 3), which had been identified earlier (4) as the major protein in human cerebrospinal fluid (CSF). PGD 2 is a major prostanoid in the brain, known as the most potent endogenous somnogenic substance thus far identified (5), and is involved in various physiological events such as regulation of sleep and pain responses (5-8). Because human L-PGDS-overexpressing transgenic mice (9) and L-PGDS-gene knock-out mice (10, 11) showed abnormality in the regulation of non-rapid eye movement (NREM) sleep and pain responses, PGD 2 produced by L-PGDS is thought to play important roles in the regulation of NREM sleep and pain sensation in the central nervous system. Alternatively L-PGDS binds small lipophilic molecules such as retinal and retinoic acid (K d ϭ 70 -80 nM) (12) and biliverdin and bilirubin (K d ϭ 33-37 nM) (13) with affinities higher than those of other members of the lipocalin family. Therefore, L-PGDS is a unique bifunctional protein acting as a PGD 2 -producing enzyme and as a lipophilic molecule-binding protein (6 -8).L-PGDS is expressed abundantly in the human heart (14), the male genital organs (15-17), and the central nervous system (18 -20) of various mammals. In the brain, this enzyme is expressed dominantly in the leptomeninges, chroid plexus, and...

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