CD206/MHCII macrophage accumulation at nerve injury site correlates with attenuation of allodynia in TASTPM mouse model of Alzheimer's disease.

Chronic pain is undertreated in people with Alzheimer's disease (AD) and better understanding of the underlying mechanisms of chronic pain in this neurodegenerative disease is essential. Neuropathic pain and AD share a significant involvement of the peripheral immune system. Therefore, we examined the development of nerve injury-induced allodynia in TASTPM (APPsweXPS1.M146V) mice and assessed monocytes/macrophages at injury site. TASTPM developed partial allodynia compared to WT at days 7, 14 and 21 days after injury, and showed complete allodynia only after treatment with naloxone methiodide, a peripheralized opioid receptor antagonist. Since macrophages are one of the sources of endogenous opioids in the periphery, we examined macrophage infiltration at injury site and observed that CD206/MHCII cells were more numerous in TASTPM than WT. Accordingly, circulating TASTPM Ly6C (classical) monocytes, which are pro-inflammatory and infiltrate at the site of injury, were less abundant than in WT. In experiments, TASTPM bone marrow-derived macrophages showed efficient phagocytosis of myelin extracts containing amyloid precursor protein, acquired CD206/MHCII phenotype, upregulated mRNA expression of proenkephalin () and accumulated enkephalins in culture media. These data suggest that in TASTPM nerve-injured mice, infiltrating macrophages which derive from circulating monocytes and may contain amyloid fragments, acquire M2-like phenotype after myelin engulfment, and release enkephalins which are likely to inhibit nociceptive neuron activity via activation of opioid receptors.