1. Academic Validation
  2. Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model

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

  • Life Sci Alliance. 2022 Sep 27;5(12):e202201555. doi: 10.26508/lsa.202201555.
Charles H Wallace 1 Giovanni Oliveros 1 Peter A Serrano 2 Patricia Rockwell 1 3 Lei Xie 4 5 Maria Figueiredo-Pereira 6 3
Affiliations

Affiliations

  • 1 PhD Program in Biochemistry, The Graduate Center, CUNY, New York, NY, USA.
  • 2 Department of Psychology, Hunter College, New York, NY, USA.
  • 3 Department of Biological Sciences, Hunter College, New York, NY, USA.
  • 4 Department of Computer Science, Hunter College, New York, NY, USA.
  • 5 Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 6 PhD Program in Biochemistry, The Graduate Center, CUNY, New York, NY, USA pereira@genectr.hunter.cuny.edu.
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.

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