Overall, the ratio of neuritic versus diffuse plaque is inversely correlated with ADAM10 activity in Tg2576/ADAM10 check details mice. This relationship is more evident when plaque morphology is compared

between 12-month-old Tg2576/DN and 20-month-old Tg2576/Q170H mice, which harbor comparable plaque loads (Figure 4D). Collectively, these findings suggest that ADAM10 activity affects not only the plaque load but plaque morphology as well. In conjunction with senile neuritic plaques, reactive gliosis is one of the key pathological markers in AD brains (Simpson et al., 2010). Compared to nontransgenic control, 18- to 20-month-old Tg2576 mice showed robust increases in microglia and astrocyte activation. The number of Iba1-positive microglia was dramatically increased in association with Congo red-stained neuritic plaques (Figures 5A and 5B), and GFAP-expressing hypertrophic astrocytes

became widespread in the cortex (Figures 5C and 5D). Glial cell activation was enhanced in Tg2576/DN mouse brains but barely detectable in Tg2576/WT mice. Tg2576/Q170H showed higher levels of gliosis than Tg2576/WT. Overall, the levels of gliosis in Tg2576/ADAM10 brains were correlated well with those of neuritic plaques. In ADAM10 single-transgenic mice, we found no notable change buy Vemurafenib in glial cell activation (Figures S4A and S4B). Taken together, these results suggest that nonamyloidogenic processing of APP by ADAM10 reduces reactive gliosis in AD pathogenesis. To further examine the physiological consequences of reduced ADAM10 activity caused by the two LOAD mutations, we tested for effects of WT versus

mutant ADAM10 on adult hippocampal neurogenesis. Recent studies have revealed that application of sAPPα increases the proliferation of neural progenitor cells (NPCs) in vitro and in vivo (Caillé et al., 2004 and Demars et al., 2011) and impairments in hippocampal neurogenesis have been linked to cognitive deficits in AD (Zhao et al., 2008). Proliferation of NPCs Baf-A1 clinical trial was analyzed by the incorporation of BrdU, a nucleotide analog, into newly born cells in the hippocampus. One day after intraperitoneal injection of BrdU, the number of BrdU-positive cells was significantly increased (48%) in the dendate gyrus of 4-month-old ADAM10-WT transgenic mice as compared to nontransgenic controls (Figures 6A and 6B). In contrast, in the Q170H and DN ADAM10 mice, the proliferation of NPCs remained at levels similar to those of the control nontransgenic mice. The level of NPC proliferation in ADAM10-R181G mice was similar compared to that of Q170H mice (data not shown). The effect of ADAM10 on differentiation of the NPCs was measured at 2 weeks after BrdU injection. Triple labeling of brain sections with anti-BrdU antibody combined with antibodies for neuronal (NeuN) and glial lineages (GFAP) revealed a 49% increase in NPC differentiation into neurons in the ADAM10-WT mice as compared to nontransgenic controls (Figures 6C and S5A).