Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer's disease.

Chao Zhou,Fang Hua,Yuqiao Wang,Xiaoyu Sun,Jingjing Han,Yuting Hu,Xinxin Yang,Zuohui Zhang,Hongjuan Shi,Yan Zhou,Xiaodong Hua,Guoliang Jin,Delian Kong,Jiaxing Song,Shuyu Dong

doi:10.18632/aging.102260

Abstract

Toll-like receptor-2 (TLR2), a member of the TLR family, plays an important role in the initiation and regulation of immune/inflammation response, which is a critical mechanism underlying Alzheimer’s disease (AD). To clarify the role of TLR2 in the pathological process of AD, in the present study, TLR2 knockout plus APPswe/PSEN1dE9 transgenic mice (AD-TLR2KO) were generated. Neurobehavioral tests and brain MRI scan were conducted on mice at the age of 12 months. Additionally, neuron loss was evaluated using NeuN staining. Amyloid β protein (Aβ), glial fibrillary acidic protein (GFAP), endogenous ligands for TLR2, and the activation of downstream signaling of TLR2 in mouse brains were detected by immunohistochemistry and Western blots. The results demonstrated that TLR2 deficit induced learning disabilities, decreased spontaneous activity, increased anxiety and depression, and led to white matter damage (WMD), brain atrophy, loss of neurons, and glial activation. Moreover, TLR2 deficit aggravated impaired neurobehavioral functions and WMD in AD mice, but did not affect the Aβ deposition in mouse brains. Our data indicate that the genomic deletion of TLR2 impairs neurobehavioral functions, induces WMD and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Aβ mechanism.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease typified by chronic inflammation and neuronal loss in the brain [1, 2]
Our data indicate that the genomic deletion of Toll-like receptor-2 (TLR2) impairs neurobehavioral functions, induces white matter damage (WMD) and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Amyloid β protein (Aβ) mechanism
Prior research has shown that AD is a heterogeneous disease involving multiple pathogenic factors, including β-amyloid deposition, tau-protein hyperphosphorylation, and inflammatory reaction, among other mechanisms [29], of which immune inflammatory response is the core pathological mechanism

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease typified by chronic inflammation and neuronal loss in the brain [1, 2]. Other candidate genes associated with AD were identified, of which the polymorphic apolipoprotein E (apoE) gene was reported to be the most related [3]. Due to these genetic mutations, the deposition of Aβ and the hyperphosphorylation of the tau-protein appear in the brain [4, 5], inducing the loss of neurons, the activation of astrocytes, and the hyperactivation of microglia cells [6, 7]. Excessive inflammation associated with the deposition of Aβ and the hyperphosphorylation of the tau-protein results in neuronal loss and white matter damage (WMD) [10,11,12]. The mechanisms underlying the regulation and modulation of inflammation in AD brains are, unclear at present

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Results

Conclusion