Exploiting formyl peptide receptor 2 to promote microglial resolution: a new approach to Alzheimer’s disease treatment

Abstract

Alzheimer’s disease and dementia are among the most significant current healthcare challenges given the rapidly growing elderly population, and the almost total lack of effective therapeutic interventions. Alzheimer’s disease pathology has long been considered in terms of accumulation of amyloid beta and hyperphosphorylated tau, but the importance of neuroinflammation in driving disease has taken greater precedence over the last 15–20 years. Inflammatory activation of the primary brain immune cells, the microglia, has been implicated in Alzheimer’s pathogenesis through genetic, preclinical, imaging and postmortem human studies, and strategies to regulate microglial activity may hold great promise for disease modification. Neuroinflammation is necessary for defence of the brain against pathogen invasion or damage but is normally self‐limiting due to the engagement of endogenous pro‐resolving circuitry that terminates inflammatory activity, a process that appears to fail in Alzheimer’s disease. Here, we discuss the potential for a major regulator and promoter of resolution, the receptor FPR2, to restrain pro‐inflammatory microglial activity, and propose that it may serve as a valuable target for therapeutic investigation in Alzheimer’s disease.

The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-κB-p65 Signaling

“…Owing to an insidious onset, long latency, and various ambiguous mechanisms, it is difficult to explore an effective therapy for AD. Among the various hypotheses for pathological mechanisms of AD [ 4 , 5 ], neuroinflammation has been the current focus of research [ 6 ].…”

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures

“…To date, most of the data indicate the expression of FPR2 on microglial cells and the unique ability of these receptors to differentiate responses based on the structure of its ligands following the described agonist bias [69,70]. Nevertheless, other authors point to the expression of FPR2 on other brain cells, including neurons, astrocytes, and even oligodendrocytes [35,71].…”

Amyloid beta and its naturally occurring N-terminal variants are potent activators of human and mouse formyl peptide receptor 1

“…Next, mFpr1 is highly upregulated in the cortex and hippocampus of transgenic APP/PS1 mice, which are a commonly used AD animal model ( 35 ). Moreover, FPR1 has been shown to mediate typical pro-inflammatory effects in glial cells that are also commonly observed in AD such as generation of oxidative stress, release of inflammatory cytokines and chemokines, and the induction of cell migration ( 14 , 35 ), whereas several reports suggest an anti-inflammatory role of FPR2 ( 41 , 44 , 60 ). Next, treatment of APP/PS1 mice with the competitive FPR antagonist tBoc2 that preferentially binds to FPR1 ( 26 ) leads to reduced microglia reactivity, decreased neuronal pathology, and improved cognitive performance ( 46 ).…”