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

Abstract

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.

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis

“…Similarly to the hippocampus [29], the ENT had higher levels of the pro-inflammatory LM PGD 2 in AD patients. PGD 2 is produced by hematopoietic PGD synthase (HPGDS), an enzyme increased in glial cells within senile plaques in AD brains [7]. Clinical trials where human AD patients are given SPMs to correct a deficiency in the levels of SPMs have not yet been performed.…”

“…Prostaglandins (PGs) and leukotrienes (LTs) are classical pro-inflammatory lipid mediators (LMs) that mediate fever and pain. PGs and LTs are biosynthesized from arachidonic acid (AA) via cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways, the activity of which have been shown to be elevated in AD [6,7]. Suppression of these pathways by inhibition or gene depletion of COX or 5-LOX successfully reduced AD-like pathologies in AD animal models [8].…”

Role of phospholipase A2s and lipid mediators in secondary damage after spinal cord injury

“…These data suggest that, in the context of SCI, PGD 2 modulates a selective number of inflammatory triggers that worsens outcome after SCI, and that PGD 2 generated via HPGDS contributes to the inflammatory response in the spinal cord and to secondary tissue damage. This synthase is also expressed in activated microglia surrounding senile plaques in Alzheimer's brains (Mohri et al 2007) and is detrimental in the mouse model of human globoid cell leukodystrophy (Mohri et al 2006). PGD 2 has also been demonstrated to mediate neuronal damage by microglia in vitro (Bate et al 2006) and might contribute to the increased neuronal sparing of ventral motor neurons after SCI in HPGDS null mice .…”

Arachidonic acid in Alzheimer's disease

“…In the brain, the most abundant prostaglandins are PGD2 and PGE2 (Figure 1, left), which are synthetized by several PGD2 and PGE2 synthases. Expression levels of hematopoietic PGD2 synthase (one of the two PGD2 synthases expressed in the brain) are enhanced in microglial cells and astrocytes of AD transgenic mice and patients 33 . As a result PGD2 is overproduced in these glial cells surrounding the amyloid plaques 33 .…”

“…Expression levels of hematopoietic PGD2 synthase (one of the two PGD2 synthases expressed in the brain) are enhanced in microglial cells and astrocytes of AD transgenic mice and patients 33 . As a result PGD2 is overproduced in these glial cells surrounding the amyloid plaques 33 . PGE2 binds to several receptors and have opposite effects on inflammation depending on the receptor type.…”