Abstract
Microglial activation plays an important role in the regulation of neuronal function and contributes to the development of neurodegeneration in Alzheimer’s disease (AD). Activation of nuclear peroxisome proliferator-activated receptor gamma (PPARγ) by an endogenous agonist, 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), has been shown to be beneficial in many diseases with aberrant immune responses. Here, we report that co-treatment with 15d-PGJ2 and its synergistic partner, 9-cis-retinoic acid (RA), may modulate, but not abolish, microglial immune response activated by β-amyloid (Aβ) and interferon gamma (IFNγ). The co-treatment of RA and 15d-PGJ2 inhibited Aβ/IFNγ-activated immune response in primary microglia, as evidenced by suppressed expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); and the effect was not affected by treatment with a PPARγ antagonist, GW9662. Data suggest that PPARγ activation may not contribute to the anti-inflammatory properties of the co-treatment. The co-treatment promoted microglial Aβ clearance in cultures; and the effect can be prevented by blocking PPARγ activation using GW9662. The effects of the co-treatment on Aβ clearance may be PPARγ-dependent. Intriguingly, secretion of microglial pro-nerve growth factor (pro-NGF) was inhibited by Aβ/IFNγ treatment in a dose-dependent manner, suggesting that secretion of microglial pro-NGF may not contribute to the Aβ/IFNγ-activated microglial immune response. Taken together, the co-treatment may be beneficial for AD therapy; however, our data suggest that multiple mechanisms may underlie the beneficial effects of the co-treatment and are not limited to PPARγ activation only.
Highlights
Alzheimer’s disease (AD) is responsible for the majority of dementia cases in the elderly
Activation of PPARγ was achieved by co-treatment of retinoic acid (RA) and 15d-PGJ2, while immune response in microglia was measured by the inductions of inflammatory proteins COX-2 and inducible nitric oxide synthase (iNOS)
Our results show that the co-treatment of RA and 15d-PGJ2 significantly reduced Aβ-induced expressions of COX-2 and iNOS in primary microglia (Table 1)
Summary
Alzheimer’s disease (AD) is responsible for the majority of dementia cases in the elderly. Microglia become activated and produce various effectors that are critical for neuronal survival during pathological events [1,2,3,4] These effectors include cytokines, chemokines, reactive oxygen and nitrogen species, prostaglandins (PGs), and neurotrophic factors [5,6,7]. PPARγ and two other genetically distinct isoforms (PPARα and PPARβ/δ) are members of a nuclear hormone receptor superfamily that are intimately involved in various regulations of gene expressions that include glucose and lipid metabolism, cell differentiation, apoptosis, inflammation, and carcinogenesis [12,13,14] It appears that transcription activity of PPARs is synergistically enhanced by heterodimer formation with retinoid X receptors (RXRα, RXRβ, RXRγ) that bind specific peroxisome proliferators response elements (PPREs) in target genes [15,16]. We used the co-treatment of ligands for RXR and PPARγ to maximize the activation of PPARγ and to investigate the effects of the cotreatment of RA and 15d-PGJ2 in primary microglia on Aβ-induced immune activation, Aβ clearance, and secretion of pro-NGF
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