The role of the CC chemokine CCL17 in a mouse model of Alzheimer’s disease

Abstract

In Alzheimer's disease (AD), inflammatory processes are critically involved by cells releasing neurotoxic or neurotrophic factors influencing survival of neurons and synapses, and thereby cognitive behavior. Several chemokines and their receptors have been shown to be upregulated in AD and play a crucial role in plaque deposition, microglia and astrocyte activation, and cognitive behavior in AD mouse models. <br /> Mice, expressing the human Amyloid precursor protein (APP) and presenilin-1 (PS1) and deficient for the endogenous CC chemokine CCL17 (APP/PS1-CCL17E/E mice) showed a WT-like learning and memory performance in Morris water maze together with reduced levels of soluble Abeta oligomers and Abeta42 peptides at 12-14 months of age, when cognitive deficits and plaque deposition are fully developed in normal APP/PS1. Surprisingly, APP/PS1-CCL17E/E mice exhibit equivalent reactive GFAP-positive astrocytes, but enhanced microgliosis. CD11b-positive microglial cells derive from CNS-resident microglia and from peripheral Ly6C(high) CCR2-positive monocytes / macrophages infiltrating the CNS of APP/PS1-CCL17E/E mice. Increased CCL22, but not CCL2 expression was found in the hippocampus of APP/PS1-CCL17E/E mice, suggesting a potential convergent recruitment mechanism of Ly6C(high) CCR2-positive CCR4-positive monocytes. For the first time, it could be demonstrated that microglia isolated from the CNS of APP/PS1 mice express CCL17. The cognate receptor CCR4 is expressed by neonatal microglia upon LPS stimulation, indicating a para- or autocrine signaling. As indicated by increased hippocampal IL-6 and IL-10 expression, APP/PS1-CCL17E/E mice showed an altered inflammatory response in the CNS. Furthermore, CCL17E/E microglia, but not macrophages, showed enhanced expression of IL-10 (in vitro) and MMR expression (in vivo). Phagocytosis assay of fluorescence-labeled Abeta1-42 peptide revealed an increased uptake by neonatal microglia, but not by BM-derived macrophages of CCL17E/E mice. <br /> The underlying mechanism possibly involves the recruitment of peripheral macrophages into the CNS, accompanied by a more anti-inflammatory and neurotrophic milieu. Furthermore, enhanced Abeta clearance is indicated by increased uptake and enhanced neprilysin expression level.