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. 2011 Mar 31;134(4):1041–1060. doi: 10.1093/brain/awr046

Figure 7.

Figure 7

2-Arachidonoyl glycerol degradation in Alzheimer’s disease and its amyloid-β1-40-induced activation. (A) Pro-inflammatory transformation by WNT-3A (300 ng/ml, 6 h) (Halleskog et al., 2011) down-regulates monoacylglycerol lipase (MGL) expression in primary mouse microglia. Interleukin-6 and tumour necrosis factor (TNF) were used as positive (internal) controls. (B) 2-Arachidonoyl glycerol is differentially metabolized in the frontal cortex in Alzheimer’s disease: Membrane-associated 2-arachidonoyl glycerol-degrading enzymatic activity is decreased, while cytosolic 2-arachidonoyl glycerol-degrading activity is significantly increased, relative to controls. (C) Membrane-associated monoacylglycerol lipase activity accounts for ∼60% of total 2-arachidonoyl glycerol hydrolysis activity as revealed by JZL184 application (Supplementary Fig. 8B and B1) in membrane samples prepared from control human specimens. Note that JZL184-sensitive 2-arachidonoyl glycerol-degrading activities are selectively lost in Alzheimer’s disease. (C1) 2-Arachidonoyl glycerol hydrolysis activity significantly increases in cytosol fractions from Alzheimer’s brains, as compared to controls. JZL184 partially reduces 2-arachidonoyl glycerol degradation in cytosolic fractions prepared from control brains and eliminates disease-associated enhancement of 2-arachidonoyl glycerol catabolism in Alzheimer’s brains (AD). (D) FAAH does not contribute to 2-arachidonoyl glycerol degradation at either subcellular fraction as tested by URB597. (E) Pre-incubation of cortical tissue homogenates from control subjects with amyloid-β1–40 (Aβ1–40) significantly increases both membrane-bound and cytosolic 2-arachidonoyl glycerol metabolism. (E1) Amyloid-β1-40 induces 2-arachidonoyl glycerol-degrading enzymatic activity in a dose-dependent manner. *P < 0.05, **P < 0.01 versus controls; ***P < 0.05, ****P < 0.01 versus non-treated samples. n/a = not analysed; NS = not significant; NT = non-treated; qPCR = quantitative polymerase chain reaction.