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 2

Microglial chemotaxis to early accumulating Aβ peptides is enhanced with Ep2 deletion in 4- to 5-month-old APP-PS1 mice.

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Microglial chemotaxis to early accumulating Aβ peptides is enhanced with...
(A) qPCR demonstrated preplaque increases in hippocampal Iba1 and Cd68 (effect of genotype, Iba1, P < 0.02; Cd68, P = 0.001; n = 5–9 per group). (B) Mip1a was increased early (effect of genotype, P = 0.01; n = 5–9 per group). (C) Decreased cerebral cortical IL-1β levels in APP-PS1 Ep2–/– versus APP-PS1 mice (n = 14–19 per group). Increased (D) Mip1a hippocampal mRNA (n = 8–13 per group) and MIP-1α cerebral cortical protein (n = 13–21 per group) and (E) Insulysin (n = 8–13 per group) in APP-PS1 Ep2–/– versus APP-PS1 brains. (F) Increased Iba1 and Cd68 mRNA in preplaque 4-month-old APP-PS1 Ep2–/– hippocampus (n = 8–13 per group). (G) Representative Aβ plaque with surrounding IBA1+ and CD68+ microglia from 5-month-old hippocampus. Dashed circle indicates area around plaques used to quantify numbers of microglia and CD68 immunofluorescence. Scale bar: 25 μm. (H) Microglia around hippocampal plaques in 5-month-old mice; average IBA1+ microglia number increased with Ep2 deletion (n = 4–7 mice per group, total 102–122 plaques per group). (I) Ep2 deletion enhanced microglial recruitment to early plaques (effect of genotype, P = 0.0016; effect of plaque size, P < 0.0001; post-hoc P < 0.05 for medium-sized plaque). Small, <250 μm2; medium, 250–575 μm2; large, >575 μm2. (J) Increased CD68 staining in periplaque hippocampal microglia of APP-PS1 Ep2–/– mice (n = 5–6 mice per genotype, total 26–48 plaques per genotype). *P < 0.05, **P < 0.01, ANOVA with Bonferroni post-hoc (A, B, and I) or Student’s t test (C–H and J).