Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist

Abstract

The cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimer's disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.

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“…25 We used the hippocampal-dependent aPAT as previously described, to assess short-term working memory performance in 9-and 11-month old WT and TgF344-AD rats. 35 The latter exhibit alterations in the hippocampal and entorhinal neuronal processes that eventually disrupt cognitive maps, thus spatial memory deficits. 36…”

“…38 IHC and its analysis was performed as previously described. 35 We viewed the sections on a Zeiss Axio Imager M2 with AxioVision software to capture ZVI files of 10x and 20x mosaic images of the whole hippocampus, and then converted to TIF files. Optical Density (O.D.)…”

“…Whole left hippocampal tissue prepared as previously described 35 was used for RNAseq analysis and was outsourced to the UCLA Technology Center for Genomics & Bioinformatics services.…”

“…was quantified using Image J as previously described. 35 Primary and secondary antibodies are listed in Supplementary Table 1. For quantification the following thresholds were used: Iba1: mean + 1.5*std, particles analyzed were in the range: 50-8,000, and circularity: 0-1.00; NeuN: mean + 1.5*std, particles analyzed were in the range: 10-10,000, and circularity: 0-1.00.…”