Neuroprotective pathways targeted by J147. Cell lysates of either hippocampal tissue or entorhinal cortex tissue from aged AD mice on control diet (AD Ctl) or J147 diet (AD J147) were analyzed by Western blotting and the images quantified in bar graphs accompanying the images. Actin was used as a loading control and all proteins were normalized to actin for quantification purposes. Protein expression levels of both pro- and mature NGF (A) are up-regulated in the hippocampus of aged huAPP/PS1 mice fed J147 in their diet for three months compared to control treated mice. (B) The ratio of pro- to mature NGF is decreased in aged huAPP/PS1 mice treated with J147. (C) Levels of another neurotrophic factor, BDNF, both pro and mature, are also increased in the hippocampus of J147 treated aged huAPP/PS1 mice. (D) The ratio of pro- to mature BDNF is decreased in aged huAPP/PS1 mice treated with J147. (E) The BDNF responsive protein Homer-1 is also increased in the hippocampus upon treatment with J147 as did Egr3 (F) another target gene of BDNF. (G) J147 stimulates neurite outgrowth promoting factor. PC12 cells were plated in growth conditioned medium (CM) prepared from HT22 cells incubated overnight plus or minus 100 nM J147, and as controls fresh DMEM plus 100 nM J147 or fresh DMEM plus 50 ng/ml NGF. Both conditioned medium from J147 treated cells and NGF promoted neurite outgrowth, while the other conditions did not. This effect was reduced by anti-NGF anti-sera. (H) BDNF is a target gene of CREB and levels of phosphorylated CREB are significantly increased in the entorhinal cortex by three months of treatment with J147 in these aged huAPP/PS1 mice. Two tailed P- values, *P <0.05, **P <0.01, and ***P <0.001. All data shown are means ± SD, N = 10 to 11 per group.