Cognitive improvement and synaptic deficit attenuation by a multifunctional carbazole-based cyanine in AD mice model through regulation of Ca2+/CaMKII/CREB signaling pathway

Chen Chen; Di Xu; Zhong-Hao Zhang; Shi-Zheng Jia; Xian-Chun Cao; Yu-Bin Chen; Guo-Li Song; Man Shing Wong; Hung Wing Li

doi:10.1016/j.expneurol.2020.113210

Cognitive improvement and synaptic deficit attenuation by a multifunctional carbazole-based cyanine in AD mice model through regulation of Ca²⁺/CaMKII/CREB signaling pathway

Exp Neurol. 2020 May:327:113210. doi: 10.1016/j.expneurol.2020.113210. Epub 2020 Jan 24.

Authors

Chen Chen¹, Di Xu², Zhong-Hao Zhang³, Shi-Zheng Jia³, Xian-Chun Cao³, Yu-Bin Chen³, Guo-Li Song⁴, Man Shing Wong⁵, Hung Wing Li⁶

Affiliations

¹ College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China; Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong, China.
² Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong, China.
³ College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
⁴ College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China; Shenzhen Bay Laboratory, Shenzhen, China. Electronic address: lilys@szu.edu.cn.
⁵ Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong, China. Electronic address: mswong@hkbu.edu.hk.
⁶ Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong, China. Electronic address: hwli@hkbu.edu.hk.

PMID: 31987831
DOI: 10.1016/j.expneurol.2020.113210

Abstract

Accumulation of β-amyloid (Aβ) peptide and hyperphosphorylated tau in the brain is one of the pathological characteristics of Alzheimer's disease (AD) and attractive therapeutic targets in its treatment. In the present study, the cognitive ability of 4-month-old 3 × Tg-AD mice significantly improved after 40 days treatment with intraperitoneal injection of 2.25 mg/kg of SLOH, which is a multifunctional carbazole-based cyanine fluorophore. It reduced Aβ deposition, tau levels and its hyperphosphorylation by modulating AKT and promoting protein phosphatase 2A activity in the brain as well as in the primary neurons of 3 × Tg-AD mice. Moreover, SLOH attenuated synaptic deficit both in vitro and in vivo by regulating the Ca²⁺/CaMKII/CREB signaling pathway. These findings strongly suggest that SLOH owns a high therapeutic potential to treat early onset AD.

Keywords: Alzheimer's disease; Aβ; Calcium pathway; Hyperphosphorylated tau; SLOH.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / metabolism
Animals
Brain / drug effects*
Brain / metabolism
Calcium / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
Carbazoles / pharmacology
Carbazoles / therapeutic use*
Cognition / drug effects
Cyclic AMP Response Element-Binding Protein / metabolism*
Disease Models, Animal
Maze Learning / drug effects*
Mice
Mice, Transgenic
Neurons / drug effects
Neurons / metabolism
Phosphorylation / drug effects
Signal Transduction / drug effects*
Synapses / drug effects*
Synapses / metabolism
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Carbazoles
Cyclic AMP Response Element-Binding Protein
tau Proteins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium