Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer’s model

Abstract

We investigated the relevance of the prostaglandin D2 pathway in Alzheimer’s disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer’s disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer’s disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer’s disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer’s disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer’s disease.

Diazoxide/dibenozylmethane treatment mitigates spatial memory deficits and pathology and upregulates protective genes in an Alzheimer’s transgenic rat model

“…Hippocampal immunohistochemistry (IHC) was performed in 4- and 11-month old rats, as previously described 25,26 . Primary and secondary antibodies used are listed in supplemental Table 1.…”

“…Ramified, reactive, and amoeboid microglia phoenotypes were analyzed for circularity based on the ImageJ form factor (FF = 4π x area/perimeter^2): ramified (FF < 0.50), reactive (FF 0.50 - 0.699), and amoeboid (FF > 0.70), where microglia with an area between 50 – 1000µm^2 were included. Microglia signal intensity (O.D) was quantified as previously 25,26 .…”

“…Pixel intensities were calculated from the images at 16-bit intensity bins. TIF files were batch processed with well-developed previously described 25,26 scripts for each channel/marker to detect positive signals, and analyzed with GraphPad Prism 9.5 (GraphPad Software, San Diego, CA).…”

Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer’s disease in females

“…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…”

“…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.…”