Limits...
Inflammatory Cyclooxygenase Activity and PGE 2 Signaling in Models of Alzheimer ’ s Disease

View Article: PubMed Central - PubMed

ABSTRACT

The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer’s disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

No MeSH data available.


Related in: MedlinePlus

Summary of inflammatory effects of the COX/PGE2/EP receptor signaling pathways in mouse mutant APP models. Modeling of EP2 and EP3 (top) and EP4 (bottom) inflammatory signaling in mouse models of AD indicates that EP2 and EP3 receptors enhance inflammatory oxidative stress, pro-inflammatory gene expression and are pro-amyloidogenic. In contrast, EP4 signaling in the setting of Aß-mediated innate immune responses is anti-inflammatory and enhances Aß phagocytosis. In preclinical AD, use of NSAIDs is preventive only in normal cognitive aging populations. Later symptomatic stages do not respond, potentially because beneficial PGE2 signaling pathways such as the EP4 receptor, as well as others including the prostacyclin (IP) receptor, are inhibited along with the toxic EP2 and EP3 pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384338&req=5

Figure 1: Summary of inflammatory effects of the COX/PGE2/EP receptor signaling pathways in mouse mutant APP models. Modeling of EP2 and EP3 (top) and EP4 (bottom) inflammatory signaling in mouse models of AD indicates that EP2 and EP3 receptors enhance inflammatory oxidative stress, pro-inflammatory gene expression and are pro-amyloidogenic. In contrast, EP4 signaling in the setting of Aß-mediated innate immune responses is anti-inflammatory and enhances Aß phagocytosis. In preclinical AD, use of NSAIDs is preventive only in normal cognitive aging populations. Later symptomatic stages do not respond, potentially because beneficial PGE2 signaling pathways such as the EP4 receptor, as well as others including the prostacyclin (IP) receptor, are inhibited along with the toxic EP2 and EP3 pathways.

Mentions: Aß peptides are highly immunogenic, and generate toxic inflammatory responses that injure synapses. Pre-clinical development of AD begins decades prior to diagnosis, and NSAIDs act during this time period to delay onset and progression to AD. The early accumulation of Aß42 peptides, beginning years to decades before cognitive symptoms arise, triggers microglial inflammatory responses that are initially robust, but falter as disease progresses. A summary of findings relevant to inflammatory actions of the PGE2 EP2, EP3, and EP4 receptors in the APP-PS1 model are diagrammed in Fig. (1). The opposing actions of the EP2/EP3 and EP4 receptors highlight the importance of targeting selected EP receptors downstream of COX-1/COX-2, as upstream inhibition of COX-1/COX-2 activity may inhibit beneficial as well as toxic PGE2 EP receptor signaling. This is a potential future indication, as we await the identification and validation of biomarkers that can reliably predict subjects at risk for AD.


Inflammatory Cyclooxygenase Activity and PGE 2 Signaling in Models of Alzheimer ’ s Disease
Summary of inflammatory effects of the COX/PGE2/EP receptor signaling pathways in mouse mutant APP models. Modeling of EP2 and EP3 (top) and EP4 (bottom) inflammatory signaling in mouse models of AD indicates that EP2 and EP3 receptors enhance inflammatory oxidative stress, pro-inflammatory gene expression and are pro-amyloidogenic. In contrast, EP4 signaling in the setting of Aß-mediated innate immune responses is anti-inflammatory and enhances Aß phagocytosis. In preclinical AD, use of NSAIDs is preventive only in normal cognitive aging populations. Later symptomatic stages do not respond, potentially because beneficial PGE2 signaling pathways such as the EP4 receptor, as well as others including the prostacyclin (IP) receptor, are inhibited along with the toxic EP2 and EP3 pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384338&req=5

Figure 1: Summary of inflammatory effects of the COX/PGE2/EP receptor signaling pathways in mouse mutant APP models. Modeling of EP2 and EP3 (top) and EP4 (bottom) inflammatory signaling in mouse models of AD indicates that EP2 and EP3 receptors enhance inflammatory oxidative stress, pro-inflammatory gene expression and are pro-amyloidogenic. In contrast, EP4 signaling in the setting of Aß-mediated innate immune responses is anti-inflammatory and enhances Aß phagocytosis. In preclinical AD, use of NSAIDs is preventive only in normal cognitive aging populations. Later symptomatic stages do not respond, potentially because beneficial PGE2 signaling pathways such as the EP4 receptor, as well as others including the prostacyclin (IP) receptor, are inhibited along with the toxic EP2 and EP3 pathways.
Mentions: Aß peptides are highly immunogenic, and generate toxic inflammatory responses that injure synapses. Pre-clinical development of AD begins decades prior to diagnosis, and NSAIDs act during this time period to delay onset and progression to AD. The early accumulation of Aß42 peptides, beginning years to decades before cognitive symptoms arise, triggers microglial inflammatory responses that are initially robust, but falter as disease progresses. A summary of findings relevant to inflammatory actions of the PGE2 EP2, EP3, and EP4 receptors in the APP-PS1 model are diagrammed in Fig. (1). The opposing actions of the EP2/EP3 and EP4 receptors highlight the importance of targeting selected EP receptors downstream of COX-1/COX-2, as upstream inhibition of COX-1/COX-2 activity may inhibit beneficial as well as toxic PGE2 EP receptor signaling. This is a potential future indication, as we await the identification and validation of biomarkers that can reliably predict subjects at risk for AD.

View Article: PubMed Central - PubMed

ABSTRACT

The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer’s disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

No MeSH data available.


Related in: MedlinePlus