Intraperitoneal Administration of Monoclonal Antibody Against Pathologic Aβ₄₂ Aggregates Alleviated Cognitive Deficits and Synaptic Lesions in APP/PS1 Mice

Article type: Research Article

Authors: Xiao, Shuo^{a; 1} | Song, Lin-Lin^{a; 1} | Li, Jiang-Tao^{a; 1} | Wang, He^a | Yu, Na^a | Wang, Zi-Qi^a | Zhang, Ying^{a; *} | He, Jin-Sheng^{a; *} | Hung, Tao^{a; b}

Affiliations: [a] College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, China | [b] Institute for Viral Disease Control and Prevention, China CDC, Beijing, China

Correspondence: [*] Correspondence to: Ying Zhang, PhD, Associate Professor, Beijing Jiaotong University, College of Life Sciences and Bioengineering, No. 3 Shangyuan Residence, Haidian District, Beijing 100044, China. Tel.: +86 10 51684351 201; Fax: +86 10 51683887; E-mail: yingzhang@bjtu.edu.cn; Jin-Sheng He, PhD, Professor, Beijing Jiaotong University, College of Life Sciences and Bioengineering, No. 3 Shangyuan Residence, Haidian District, Beijing 100044, China. Tel.: +86 10 51684080; Fax: +86 10 51683887; E-mail: jshhe@bjtu.edu.cn.

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is the most common form of dementia, characterized by amyloid-β peptide (Aβ) aggregates, phosphorylated tau protein (p-tau), and progressive neurodegeneration. Amyloid-β peptide 42 (Aβ42) is considered an early trigger of AD pathogenesis. We have previously reported that Aβ N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aβ in the brains of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1ΔE9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aβ and p-tau in the brains of APP/PS1 mice. Regarding Aβ levels, western blot results showed that Aβ42 oligomer (p < 0.01) but not Aβ40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231) (p < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade.

Keywords: Alzheimer’s disease, amyloid-β peptide, immunotherapy, Morris water maze test, phosphorylated tau protein, synapse

DOI: 10.3233/JAD-190874

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 657-670, 2020