Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson
Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson
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Research Article Neuroscience

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Abstract

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

Authors

Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson

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Figure 6

Inhibition of microglial EP2 signaling decreases inflammation and rescues memory following i.c.v. Aβ42 administration.

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Inhibition of microglial EP2 signaling decreases inflammation and rescue...
(A) Cluster analysis producing separation for genotype and treatment is shown for 22 immune factors in cerebral cortex that were significantly upregulated in hippocampus 48 hours after i.c.v. Aβ42. Asterisks denote factors that were differentially regulated by microglial EP2 (see Supplemental Figure 5). (B) Overview of the NOR memory test, with the novel object shaded green. (C) DI (comparing 0-hour training session with 24-hour recognition session) demonstrated normal memory consolidation in control i.c.v. vehicle–treated Cd11b-Cre and Cd11b-Cre Ep2fl/fl mice, and absence of memory consolidation in the i.c.v. Aβ42–treated Cd11b-Cre cohort, which was significantly rescued by microglial Ep2 deletion in the i.c.v. Aβ42–treated Cd11b-Cre Ep2fl/fl cohort (n = 8–15 mice per group; **P < 0.01, *P < 0.05, paired 1-tailed Student’s t test).