Icariin Attenuates M1 Activation of Microglia and Aβ Plaque Accumulation in the Hippocampus and Prefrontal Cortex by Up-Regulating PPARγ in Restraint/Isolation-Stressed APP/PS1 Mice

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

Various environmental and genetic factors influence the onset and progression of Alzheimer's disease (AD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating levels of glucocorticoid hormones, occurs early in AD, resulting in increased cortisol levels. Disturbances of the HPA axis have been associated with memory impairments and may contribute to the cognitive decline that occurs in AD, although it is unknown whether such effects involve modulation of the amyloid beta-peptide (Abeta) and tau. Using in vitro and in vivo experiments, we report that stress-level glucocorticoid administration increases Abeta formation by increasing steady-state levels of amyloid precursor protein (APP) and beta-APP cleaving enzyme. Additionally, glucocorticoids augment tau accumulation, indicating that this hormone also accelerates the development of neurofibrillary tangles. These findings suggest that high levels of glucocorticoids, found in AD, are not merely a consequence of the disease process but rather play a central role in the development and progression of AD.

Abstract: Macrophages, a key component of the innate defense against pathogens, participate in the initiation and resolution of inflammation, and in the maintenance of tissues. These diverse and at times antithetical functions of macrophages are executed via distinct activation states, ranging from classical to alternative to deactivation. Because the dysregulation of macrophage activation is pathogenically linked to various metabolic, inflammatory and immune disorders, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. Here, the mechanisms by which peroxisome proliferator-activated receptors (PPARs) transcriptionally regulate macrophage activation in health and disease states, including obesity, insulin resistance and cardiovascular disease, are reviewed.