Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer%26apos;s disease

作者：Cimino Patrick J^*; Yang Yue; Li Xianwu; Hemingway Jake F; Cherne Makenzie K; Khademi Shawn B; Fukui Yoshinori; Montine Kathleen S; Montine Thomas J; Keene C Dirk

来源：Experimental and Molecular Pathology, 2013, 94(2): 366-371.

DOI：10.1016/j.yexmp.2013.01.002

• Innate immunity
• Microglia
• Amyloid beta
• PGE2 receptor EP2
• Alzheimer%26apos
• s disease

Alzheimer%26apos;s disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE(2)) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE(2) receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (A beta) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-A beta effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 -/-), were hemizygous for DOCK2 (DOCK2 +/-), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1 Delta e9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1 Delta e9 mice, cerebral cortical and hippocampal A beta plaque area and size were significantly reduced in 10-month-old APPswe-PS1 Delta e9/DOCK2-/- mice compared with APPswe-PS1 Delta e9/DOCK2+/+ controls. DOCK2 hemizygous APPswe-PS1 Delta e9 mice had intermediate A beta plaque levels. Interestingly, soluble A beta(42) was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar A beta. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to A beta plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.

• 出版日期2013-4