CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function

Chul Ju Hwang,Sang Yeon Oh,Ju Hwan Kim,Sang-Bae Han,Ki-Wan Oh,Dae Yeon Hwang,Mi Hee Park,Ju Kyung Song,Yun-Bae Kim,Na Young Yun,Hyun Ok Seo,Jin Tae Hong,Jae Yeon Hwang

doi:10.18632/oncotarget.7453

Chul Ju Hwang, Sang Yeon Oh + Show 11 more

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https://doi.org/10.18632/oncotarget.7453

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Abstract

Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aβ) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aβ deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of β-secretase as well as Aβ deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 μg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aβ level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment.

Highlights

Pathological features that appear in the brain of Alzheimer disease (AD) patients include deposition of amyloid plaques, neuronal and synaptic loss and activation of astrocytes [1,2,3,4,5]
There is more severe memory impairment previous data (LPS non-injection group) when after LPS injection in present study (Supplementary Table 1). These results indicate that the ability of acquisition and recalling of memory was lowered by LPS-injection, and the memory impairment was higher in LPS-injected chemokine receptor 5 (CCR5)-/- mice compared with that of LPS-injected CCR5+/+ mice
It was shown that the deficiency of CCR5 in LPS treated CCR5-/- mice resulted in the dysfunction of memory capacity

Summary

Introduction

Pathological features that appear in the brain of AD patients include deposition of amyloid plaques, neuronal and synaptic loss and activation of astrocytes [1,2,3,4,5]. Recent data indicated that astrocytes may act as a source for Aβ because they overexpress β-secretase (BACE1), an enzyme that cleaves amyloid precursor protein (APP) to produce Aβ [8] These studies suggest that activated astrocytes contribute to the synthesis of Aβ and progress of AD. Chemokines are produced upon activation by a wide www.impactjournals.com/oncotarget spectrum of inflammatory cell types including astrocytes [9, 10]. Several chemokines, and their receptors and ligands have been found to be upregulated in the AD brain [11]. These findings suggest that chemokines, and their receptors and ligands may contribute to the development and/or the progression of AD through modification of astrocyte activation

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