Journal Article

Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer’s Disease

Zhu, Qiwen, Zhu, Chunyan, Xu, Bing, Sun, Xiaohong, Sui, Yi

2017

Overview

The majority of Alzheimer’s disease (AD) patients have a late onset, and chronic neuroinflammation, characterized by glial activation and secretion of pro-inflammatory cytokines and chemokines, plays a role in the pathogenesis of AD. The chemokine CCL11 has been shown to be a causative factor of cognitive decline in the process of aging, but little is known whether it is involved in the pathogenesis of AD. In the present study, we showed that CCR3, the receptor for CCL11, was expressed by hippocampal neurons and treatment of primary hippocampal neuronal cultures (14 days in vitro) with CCL11 resulted in activation of cyclin-dependent kinase 5 and glycogen synthase kinase-3β, associated with elevated tau phosphorylation at multiple sites. CCL11 treatment also induced the production of Aβ and dendritic spine loss in the hippocampal neuronal cultures. All these effects were blocked by the CCR3 specific antagonist, GW766994. An age-dependent increase in CCL11, predominantly expressed by the activated microglia, was observed in the cerebrospinal fluid of both APP/PS1 double transgenic mice and wild-type (WT) littermates, with a markedly higher level in APP/PS1 double transgenic mice than that in WT littermates. Deletion of CCR3 in APP/PS1 double transgenic mice significantly reduced the phosphorylation of CDK5 and GSK3β, tau hyperphosphorylation, Aβ deposition, microgliosis, astrogliosis, synaptic loss, and spatial learning and memory deficits. Thus, the age-related increase in CCL11 may be a risk factor of AD, and antagonizing CCR3 may bring therapeutic benefits to AD.

• Publisher: Springer US,Springer Nature B.V
• Subject: Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid / Amyloid beta-Peptides - metabolism / Animals / Biomedical and Life Sciences / Biomedicine / Cell Biology / Cerebrospinal fluid / Chemokine CCL11 - pharmacology / Chemokines / Clonal deletion / Cognitive ability / Cyclin-dependent kinase / Cyclin-dependent kinase 5 / Cyclin-dependent kinases / Cytokines / Dendritic spines / Disease Models, Animal / Gliosis / Glycogen / Glycogen synthase kinase 3 / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 beta - metabolism / Hippocampus / Hippocampus - drug effects / Hippocampus - metabolism / Inflammation / Kinases / Memory Disorders - metabolism / Memory Disorders - physiopathology / Mice, Transgenic / Microglia / Neurobiology / Neurodegenerative diseases / Neurology / Neuronal-glial interactions / Neurons / Neurons - metabolism / Neurosciences / Pathogenesis / Phosphorylation / Phosphorylation - drug effects / Presenilin 1 / Receptors, CCR3 - drug effects / Receptors, CCR3 - metabolism / Rodents / Secretion / Spatial discrimination / Spatial discrimination learning / Spatial Learning - physiology / Spatial memory / tau Proteins - drug effects / tau Proteins - metabolism / Transgenic animals / Transgenic mice