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Article Title: Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist
Figure Legend Snippet: Scheme depicting the relevance of the PGD2 pathway to AD and its potential as a novel multitarget therapeutic for AD Tg-AD rats at 11 months of age exhibited a microglia shift in the hippocampus, from a neuroprotective state typical of ramified microglia to more of a neurotoxic and overactive state attributable to amoeboid microglia. DP1/microglia co-localization at the hippocampal hilar subregion followed the same pattern, increasing the most in amoeboid microglia. Tg-AD rats also displayed DP2 and neuronal losses in the hippocampus. In the brains of AD patients, L-PGDS, the major PGD2 synthase in the brain, is upregulated and Sox-2, a transcription factor, is downregulated. We propose that manipulating PGD2 signaling through, for example DP2 receptor antagonists such as timapiprant, could prevent/mitigate AD neuropathology. DP1 agonists via cAMP convert microglia to a tissue reparative phenotype, protect the brain from ischemic stroke by facilitating vasodilation, and promote sleep that drives Aβ clearance. DP1 antagonists protect against hemorrhagic stroke by limiting bleeding, and mitigate neurotoxic microglia levels. DP2 antagonists prevent neuronal loss, act as antidepressants and improve cognition, potentially via inhibition of the PI3K/AKT/mTOR pathway. L-PGDS, the major PGD2 synthase in the brain, also acts as an Aβ chaperone, inhibits Aβ40/42 aggregation, functions as a disaggregase by disassembling Aβ fibrils, and modulates the expression of Sox-2, a transcription factor. Sox-2 protects against AD neuropathology by interacting with APP and promoting α-secretase activity. Further details are presented in the discussion, based on our current results with the Tg-AD rat model and studies published by others. Figure partially created with BioRender.com .
Techniques Used: Inhibition, Expressing, Activity Assay
Figure Legend Snippet: Timapiprant mitigates AD pathology. Tg-AD timapiprant-treated (TGTR, n = 9) compared to Tg-AD nontreated (TGNT, n = 9) male rats perform significantly better in latency to first entrance during training ( a , p = 0.002) with a significant post-hoc difference on trial 5, experience lower plaque burden ( b , p = 0.001), higher neuronal levels ( c , p = 0.01), and lower microglia levels ( d , p
Figure Legend Snippet: Schematic representation of the experimental design a Time line of the progression of the AD pathology developed by Tg-AD rats. b Rat groups used in the study. c Assessments of the AD pathology developed by the Tg-AD rats at 11 months of age. d Timapiprant treatment overview.