Neuroplastin 65 deficiency reduces amyloid plaque formation and cognitive deficits in an Alzheimer's disease mouse model

Dan-Dan Wu; Jie Cheng; Ya-Ni Zheng; Yu-Tong Liu; Shuang-Xin Hou; Li-Fen Liu; Liang Huang; Qiong-Lan Yuan

doi:10.3389/fncel.2023.1129773

Neuroplastin 65 deficiency reduces amyloid plaque formation and cognitive deficits in an Alzheimer's disease mouse model

Front Cell Neurosci. 2023 May 5:17:1129773. doi: 10.3389/fncel.2023.1129773. eCollection 2023.

Authors

Dan-Dan Wu¹, Jie Cheng¹, Ya-Ni Zheng¹, Yu-Tong Liu², Shuang-Xin Hou³, Li-Fen Liu¹, Liang Huang^{1

4}, Qiong-Lan Yuan^{1

4}

Affiliations

¹ Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
² Department of Radiology, University of Nebraska Medical Center, Omaha, NE, United States.
³ Department of Neurobiology, Shanghai Pudong Hospital, Fudan University, Shanghai, China.
⁴ Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, China.

Abstract

Introduction: Alzheimer's disease (AD) is characterized by increasing cognitive dysfunction, progressive cerebral amyloid beta (Aβ) deposition, and neurofibrillary tangle aggregation. However, the molecular mechanisms of AD pathologies have not been completely understood. As synaptic glycoprotein neuroplastin 65 (NP65) is related with synaptic plasticity and complex molecular events underlying learning and memory, we hypothesized that NP65 would be involved in cognitive dysfunction and Aβ plaque formation of AD. For this purpose, we examined the role of NP65 in the transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD.

Methods: Neuroplastin 65-knockout (NP65^-/-) mice crossed with APP/PS1 mice to get the NP65-deficient APP/PS1 mice. In the present study, a separate cohort of NP65-deficient APP/PS1 mice were used. First, the cognitive behaviors of NP65-deficient APP/PS1 mice were assessed. Then, Aβ plaque burden and Aβ levels in NP65-deficient APP/PS1 mice were measured by immunostaining and western blot as well as ELISA. Thirdly, immunostaining and western blot were used to evaluate the glial response and neuroinflammation. Finally, protein levels of 5-hydroxytryptamin (serotonin) receptor 3A and synaptic proteins and neurons were measured.

Results: We found that loss of NP65 alleviated the cognitive deficits of APP/PS1 mice. In addition, Aβ plaque burden and Aβ levels were significantly reduced in NP65-deficient APP/PS1 mice compared with control animals. NP65-loss in APP/PS1 mice resulted in a decrease in glial activation and the levels of pro- and anti-inflammatory cytokines (IL-1β, TNF-α, and IL-4) as well as protective matrix YM-1 and Arg-1, but had no effect on microglial phenotype. Moreover, NP65 deficiency significantly reversed the increase in 5-hydroxytryptamine (serotonin) receptor 3A (Htr3A) expression levels in the hippocampus of APP/PS1 mice.

Discussion: These findings identify a previously unrecognized role of NP65 in cognitive deficits and Aβ formation of APP/PS1 mice, and suggest that NP65 may serve as a potential therapeutic target for AD.

Keywords: 5-hydroxytryptamine receptor 3A subunit; Alzheimer’s disease; amyloid plaques; glial activation; neuroinflammation; neuroplastin 65.

Grants and funding

This work was supported by the National Natural Science Foundation of China (81371213 and 81070987) and by grants from the Natural Science Foundation of Shanghai (21ZR1468400).