CCL17-deficiency alters myeloid cell-responses and prevents cognitive decline in APP/PS1-mice

The CC-chemokine CCL17 regulates leukocyte trafficking during inflammation, however, its role in Alzheimerʼs disease (AD) pathogenesis remains undefined. Here we show that CCL17 is enhanced in AD patients when compared to healthy controls. In a mouse model for AD we found that CCL17 controls amyloid β (Aβ) deposition, neuroinflammation, and cognitive decline. CCL17 deficient APP/PS1 mice (APP/PS1-CCL17E/E) showed reduced Aβ brain levels, and were protected against neuronal loss and cognitive deficits. Enhanced microgliosis and brain recruitment of Ly6C+CCR2+ macrophages expressing mannose receptors associated with elevated brain IL-10 levels pointed to beneficial immune responses in these mice. In the absence of CCL17 we observed accelerated uptake of Aβ, enhanced IL-10 release by activated microglia and upregulated Aβ-degrading enzyme neprilysin (NEP) in APP/PS1 brains. These newly identified roles for CCL17 in regulating microglia function and memory loss suggest that targeting this chemokine may harbor therapeutic potential for the treatment of AD.