First Author | Raman D | Year | 2011 |
Journal | Toxicol Appl Pharmacol | Volume | 256 |
Issue | 3 | Pages | 300-13 |
PubMed ID | 21704645 | Mgi Jnum | J:178566 |
Mgi Id | MGI:5299284 | Doi | 10.1016/j.taap.2011.06.006 |
Citation | Raman D, et al. (2011) Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1alpha, suppress amyloid beta-induced neurotoxicity. Toxicol Appl Pharmacol 256(3):300-13 |
abstractText | Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-beta (Abeta). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1alpha (SDF-1alpha), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Abeta-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1alpha significantly protected neurons from Abeta-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1alpha. Intra-cerebroventricular (ICV) injection of Abeta led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24h following the exposure. The Abeta-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F(2)-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1alpha. Additionally, MIP-2 or SDF-1alpha was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against Abeta neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. |