Functional Compensation and Mechanism of Choline Acetyltransferase in the Treatment of Cognitive Deficits in Aged Dementia Mice

Zhenxia Zhu; Lulu Zhang; Yali Cui; Meng Li; Rutong Ren; Guoxing Li; Xin Sun; Qian Li

doi:10.1016/j.neuroscience.2020.05.016

Functional Compensation and Mechanism of Choline Acetyltransferase in the Treatment of Cognitive Deficits in Aged Dementia Mice

Neuroscience. 2020 Aug 21:442:41-53. doi: 10.1016/j.neuroscience.2020.05.016. Epub 2020 Jun 1.

Authors

Zhenxia Zhu¹, Lulu Zhang², Yali Cui², Meng Li², Rutong Ren², Guoxing Li², Xin Sun², Qian Li³

Affiliations

¹ Capital Medical University Electric Power Teaching Hospital, No 1 Taipingqiaoxili, Beijing 100073, China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
³ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China. Electronic address: bjliqian@sina.com.

PMID: 32497760
DOI: 10.1016/j.neuroscience.2020.05.016

Abstract

Choline acetyltransferase (ChAT) synthesizes the neurotransmitter acetylcholine (Ach). Exogenous supplementation with ChAT can functionally compensate for decreased Ach levels and ameliorate memory and cognitive deficits. In this paper, the treatment efficacy of recombinant ChAT (peptide transduction domain (PTD)-ChAT) and donepezil were compared in aged dementia mice, and their mechanisms were explored by performing the gene function annotation and enrichment analysis of differentially expressed genes. The Morris water maze test showed that the swimming times of PTD-ChAT-treated (4 mg/kg) and donepezil-treated (0.5 mg/kg) mice with mild and moderate dementia were significantly shortened (P < 0.01 vs aged dementia mice), and no significant changes were observed between the PTD-ChAT- and donepezil-treated groups. In contrast, the swimming times of PTD-ChAT-treated mice with severe dementia were noticeably shorter than those of donepezil-treated mice with severe dementia (P < 0.01), indicating that the treatment efficacy of PTD-ChAT is superior to that of donepezil. The effect of PTD-ChAT was further confirmed in transgenic dementia mice (C57BL/6J-TgN (APP/PS1) ZLFILAS). Gene function annotation and enrichment analysis showed that PTD-ChAT improved cognitive deficits through Ach and was implicated in neuroprotection, synaptic plasticity, neuronal survival, and cerebrovascular remodeling through ACh and vascular endothelial growth factor (VEGF) pathway activation. Donepezil was significantly correlated with the immune inflammatory response and the insulin and IGF-1 signaling pathways. Therefore, although PTD-ChAT and donepezil were both effective in the treatment of aged dementia mice, their mechanisms were significantly different. Our research indicated that PTD-ChAT has potential promise for research on new drugs for AD treatment.

Keywords: Alzheimer’s disease; acetylcholine; aged dementia mice; anti-inflammatory pathway; choline acetyltransferase; donepezil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Choline O-Acetyltransferase*
Cognition
Dementia* / drug therapy
Mice
Mice, Inbred C57BL
Vascular Endothelial Growth Factor A

Substances

Vascular Endothelial Growth Factor A
Choline O-Acetyltransferase