Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity

Abstract

Alzheimer’s disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-β (Aβ). 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-1α (SDF-1α), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress Aβ-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1α significantly protected neurons from Aβ-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1α. Intra-cerebroventricular (ICV) injection of Aβ led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The Aβ-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F2-isoprostanes, was significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1α. Additionally, MIP-2 or SDF-1α 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 Aβ 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.

The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects

“…Intracerebroventricular (icv) injections of Aβ in mice lowered spine density and dendrite length of CA1 hippocampal neurons, while pretreatment with CXCL12, through activation of AKT and ERK1/2 pathways, inhibited this Aβ‐induced neurotoxicity. Similar results were found in vitro in cultured neurons . Finally, treatment of APP/PS1 mice with CXCL12 (intracerebroventricular injection) induced the recruitment of bone marrow–derived microglia (a well‐known role of CXCL12) to the brain, which is thought to be neuroprotective, contrary to activated resident CNS microglia.…”

Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model

“…Supporting this treatment with anti-SDF-1 blocking serum resulted in a marked impairment in migration and proliferation of engrafted neural stem cells [25]. Besides stimulation of cell migration, SDF-1a is able to promote neurite outgrowth of cultured neurons [12] and to protect neurons from apoptosis after ß-amyloid-induced neurodegeneration [26].…”

Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair

“…Therefore, inhibited CXCL12-CXCR4 signaling in AD patients might impact the normal neuronal survival advantage conferred by CXCL12. Pretreatment with CXCL12 in culture can significantly protect neurons from Aβ-induced dendritic regression and apoptosis through activation of AKT and ERK1/2 pathways [104]. Intra-cerebroventricular injection of Aβ reduces dendritic length and spine density of pyramidal neurons in the hippocampus CA1 area, and this deleterious effect can be significantly inhibited by direct application of CXCL12 [104].…”

“…Pretreatment with CXCL12 in culture can significantly protect neurons from Aβ-induced dendritic regression and apoptosis through activation of AKT and ERK1/2 pathways [104]. Intra-cerebroventricular injection of Aβ reduces dendritic length and spine density of pyramidal neurons in the hippocampus CA1 area, and this deleterious effect can be significantly inhibited by direct application of CXCL12 [104]. These studies suggest that increasing the ambient CNS concentration of CXCL12 may be considered as a strategy to treat AD patients, since CXCL12 is down-regulated in both patients and experimental animals.…”