We also described, using z-score analysis, preferential expression of this set of KDM5A targets in human tissues

oring memory of the platform location to control levels. J147 Reduces Soluble Ab Levels in the Hippocampus Since some compounds that reduce memory loss in AD mice reduce Ab plaque burden, we next examined plaque size and density as well as Ab levels in the RIPA insoluble and soluble fractions of the hippocampi of J147 treated and control huAPP/PS1 mice. Neither Ab142 nor Ab140 levels as measured by ELISA, were altered in the RIPA insoluble fraction in animals fed J147 relative to untreated AD transgenic animals. Although there was no difference in plaque size between control and J147 treated animals, the average area occupied by plaques and the total number of plaques in each group was significantly different. Therefore, while treatment with J147 enhanced the cognitive ability of the huAPP/PS1 mice, it had no significant effect on insoluble Ab levels but a small but significant reduction of plaque load. However, it is now thought that soluble Ab polymers are major contributors to the toxicity associated with the peptide. 7 December 2011 | Volume 6 | Issue 12 | e27865 A Cognitive Enhancing Drug For Alzheimer’s BAY-41-2272 Disease J147 Reduces Oxidative Stress and the Inflammatory Response significant part of the inflammatory immune response in the CNS and are activated and increased in number in AD. Biochemical markers for microglia include Iba-1 and inducible nitric oxide synthase. J147 Reduces Heat-Shock Proteins and Increases Synaptic Protein Expression Oxidative stress damages proteins and degrades their ability to fold properly. To compensate, cells increase the synthesis of proteins that promote proper folding, including members of the December 2011 | Volume 6 | Issue 12 | e27865 A Cognitive Enhancing Drug For Alzheimer’s Disease with both human AD and behavioral deficits in transgenic mouse lines;;. BDNF ” is Up-Regulated by J147 23505071” J147 was synthesized and selected for its ability to act as a neurotrophic factor in part using assays where it can replace the function of BDNF. It was therefore asked if J147 is able to increase December 2011 | Volume 6 | Issue 12 | e27865 A Cognitive Enhancing Drug For Alzheimer’s Disease the expression of BDNF and/or activate one or more of its downstream signaling pathways. J147 increases the levels of BDNF in the hippocampus of both normal rats as well as in huAPP/PS1 transgenic mice. BDNF directly regulates the expression of several genes involved in synaptic spine formation as well as the phosphorylation of proteins involved in learning and memory. Homer 1 is an actin binding protein that is induced by BDNF. the expression of this protein relative to untreated huAPP/PS1 mice. The phosphorylation of the scaffold protein PSD95 is mediated by BDNF. 10 December 2011 | Volume 6 | Issue 12 | e27865 A Cognitive Enhancing Drug For Alzheimer’s Disease Together these results show that J147 both increases BDNF levels and modulates the expression and/or phosphorylation of downstream targets of BDNF. Discussion Familial AD is caused by mutations in a small subset of genes that control the generation of Ab. Because of these findings, it is widely believed that Ab is the causative factor in AD and the vast majority of the drug development effort for AD is focused upon Ab or components of the Ab biosynthetic pathway. While Ab is clearly relevant, over 95% of all AD cases are not FAD and age is by far the greatest risk factor for the disease. It is therefore likely that the various pathological components of old age such as oxi