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Regenerative potential of M2-polarized anti-inflammatory macrophages in the context of inflammation-based neurodegeneration in a model of APP?+ Alzheimer disease

Fred Fändrich

Lately, there is accumulating evidence evidence for silent inflammation as a major contributor to Alzheimer Disease (AD), associated as one potential underlying pathomechanism. This includes innate immunity, specifically M1-polarised inflammatory macrophages which trespass the blood brain barrier.  Using wild-type and amyloid precursor protein β protein transduced mice we compared the cognitive abilities of four different experimental groups (n=8). 1. Wild type mice (not transduced with APPβ), 2. APPβ+ animals treated with saline, 3. APPβ+ mice treated with radiated (7 gy) REMs (M2-polarized anti-inflammatory macrophages), and 4. APPβ+ mice treated with non-radiated REMs. REMs (radiated and non-radiated) were injected intravenously into APPβ+ animals at the age of 2 months. Cognitive capacity was tested using a water-maze and labyrinth test model, at the age of two months (young mice) and at 6 months (old mice) of age. We found a significant reduced capacity of learning and orientation capacities in all four groups when comparing young and old mice. There was a significant cognitive decline when comparing wild-type animals with APPβ+ animals treated with saline (p<0.01) or radiated REMs (p<0.01). Treatment with non-radiated REMs prevented the development of AD in all 8 animals tested whose cognitive functional scores did not differ significantly from wild-type animals. In a pilot observation n=7 Alzheimer patients were treated with autologous REM´s generated from patient’s monocytes. Based on MMSE (MINI-Mental-State-Examination) n=4 patients had an improvement of the cognitive activity. Our results indicate that the anti-inflammatory properties of regenerative M2-polarized REM macrophages is able to prevent astrocyte and microglial activation in APPβ+ animals and underscores silent inflammatory-based neuronal damage as a major pathomechanism in this animal model. Additionally, first clinical results show that this cellular therapy has a positive effect on the cognitive activity of Alzheimer patients.