Late-Stage Activation of Toll-like receptor 3 Alleviates Cognitive Impairment and Neuropathology in an Alzheimer's Disease Mouse Model

Taiyang Zhu; Fanyu Shen; Xiao Jia; Hui Zhou; Wanyan Ni; Shang Wang; Di Wu; Huimin Gao; Zhenying Shang; Yan Zhou; Jingjing Han; Guoliang Jin; Fuxing Dong; Jie Zu; Xinxin Yang; Hongjuan Shi; Chao Zhou; Fang Hua

doi:10.1007/s12035-025-05092-0

Late-Stage Activation of Toll-like receptor 3 Alleviates Cognitive Impairment and Neuropathology in an Alzheimer's Disease Mouse Model

Mol Neurobiol. 2025 May 28. doi: 10.1007/s12035-025-05092-0. Online ahead of print.

Authors

Taiyang Zhu^{1

2}, Fanyu Shen^{1

2}, Xiao Jia^{1

2}, Hui Zhou^{1

2}, Wanyan Ni^{1

2}, Shang Wang³, Di Wu⁴, Huimin Gao^{1

2}, Zhenying Shang², Yan Zhou^{1

2}, Jingjing Han^{1

2}, Guoliang Jin^{1

2}, Fuxing Dong⁵, Jie Zu^{1

2}, Xinxin Yang^{1

2}, Hongjuan Shi^{1

2}, Chao Zhou^{6

7}, Fang Hua^{8

9}

Affiliations

¹ Department of Neurology, Xuzhou Medical University, Xuzhou, 221004, China.
² Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
³ Department of Human Anatomy, Kangda College of Nanjing Medical University, Lianyungang, 222000, China.
⁴ Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, China.
⁵ Public Experimental Research Center, Xuzhou Medical University, Xuzhou, 221004, China.
⁶ Department of Neurology, Xuzhou Medical University, Xuzhou, 221004, China. zhouchao@njglyy.com.
⁷ Department of Neurology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, China. zhouchao@njglyy.com.
⁸ Department of Neurology, Xuzhou Medical University, Xuzhou, 221004, China. fhua@augusta.edu.
⁹ Department of Interdisciplinary Health Science, College of Allied Health Science, Augusta University, Augusta, GA, 30912, USA. fhua@augusta.edu.

PMID: 40437286
DOI: 10.1007/s12035-025-05092-0

Abstract

This study was to investigate the effects of Toll-like receptor-3 (TLR3) activation on cognitive impairment and neuropathology in late-stage of Alzheimer's disease in a mouse model. Amyloid protein precursor (APP)/presenilin-1 (PSEN1) (APP/PSEN1) mice were treated with Poly (I:C), a specific for TLR3. A panel of neurobehavioral tests were conducted to evaluate their cognitive functions. Aβ deposition, plasma Aβ levels, neuropathological changes, and activation of TLR3- TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling were assessed by magnetic resonance imaging (MRI), electrophysiological recordings, transmission electron microscopy, Western blotting, immunofluorescence staining, and qPCR. The data demonstrated that Poly (I:C) significantly attenuated cognitive and neuropathological impairments, compared with APP/PSEN1 mice without Poly (I:C) treatment. Administration of Poly (I:C) significantly reduced brain Aβ_1-42 deposition and the levels of Aβ_1-40 and Aβ_1-42 in peripheral blood. In addition, treatment with Poly (I:C) significantly up-regulated the expression of anti-inflammatory factors and inhibited the expression of pro-inflammatory factors. The data indicated that systemic application of TLR3 agonist Poly(I:C) attenuated the brain damage, improved the cognitive function, and reduced the levels of Aβ_1-42 in brain and peripheral blood. The underlying mechanism might attribute to the up-regulation of p-IRF3 that increases the expression of anti-inflammatory factors and the inhibition of p-NF-κB that reduces the expression of pro-inflammatory factors.

Keywords: Alzheimer’s disease; Mouse model; Poly (I:C); TRIF; Toll-like receptor-3.

Grants and funding

82171420/National Nature Science Foundation of China