Untangling the Web: Toxic and Protective Effects of Neuroinflammation and PGE₂ Signaling in Alzheimer’s Disease

Abstract

The neuroinflammatory response has received increasing attention as a key factor in the pathogenesis of Alzheimer’s disease (AD). Microglia, the innate immune cells and resident phagocytes of the brain, respond to accumulating Aβ peptides by generating a nonresolving inflammatory response. While this response can clear Aβ peptides from the nervous system in some settings, its failure to do so in AD accelerates synaptic injury, neuronal loss, and cognitive decline. The complex molecular components of this response are beginning to be unraveled, with identification of both damaging and protective roles for individual components of the neuroinflammatory response. Even within one molecular pathway, contrasting effects are often present. As one example, recent studies of the inflammatory cyclooxygenase–prostaglandin pathway have revealed both beneficial and detrimental effects dependent on the disease context, cell type, and downstream signaling pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenases, are associated with reduced AD risk when taken by cognitively normal populations, but additional clinical and mouse model studies have added complexities and caveats to this finding. Downstream of cyclooxygenase activity, prostaglandin E2 signaling exerts both damaging pro-inflammatory and protective anti-inflammatory effects through actions of specific E-prostanoid G-protein coupled receptors on specific cell types. These complexities underscore the need for careful study of individual components of the neuroinflammatory response to better understand their contribution to AD pathogenesis and progression.

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

“…Interestingly, these beneficial effects were inversely related to prostaglandin-E2 levels, but did not depend upon decreased Aβ production or the inflammatory cytokines TNF-α and IL-1β. These results highlight the importance of downstream prostaglandin signaling in AD pathogenesis [22].…”

PGE 2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia

“…It is interesting to note that inhibition of COX-2 as far out as 18 h after MCAo is also effective in limiting stroke damage in models of stroke (45), a time window that coincides with the poststroke inflammatory response. Of the four PGE 2 receptors, maladaptive innate immune responses have been established for the EP2 receptor and include a persistence of proinflammatory responses from induction of COX-2 expression and PGE 2 generation, a suppression of phagocytosis and lysosomal function, and an inhibition of neurotrophic support (4,15,46). Conversely, the EP4 receptor is highly anti-inflammatory (3) in addition to being neuroprotective and vasodilatory in stroke models (2).…”

The endocytic pathway in microglia during health, aging and Alzheimer’s disease

“…Targeting downstream of COX might avoid this detrimental response (Johansson et al, 2015). This topic has been reviewed in detail (Woodling and Andreasson, 2016). …”