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Catalpol Ameliorates Neurotoxicity in N2a/APP695swe Cells and APP/PS1 Transgenic Mice

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Abstract

Alzheimer’s disease (AD) causes progressive decline of memory and cognitive deficits. Because of its complicated pathogenesis, the prevention and therapy of AD remain an enormous challenge. It has been reported that catalpol possessed neuroprotective effects against AD. However, the involved mechanism still needs to be intensively studied. Therefore, the effects of catalpol on N2a/APP695swe cells and APP/PS1 mice were identified in the current study. Catalpol could improve cytotoxicity according to CCK-8 assay and ameliorate cellular morphological changes in N2a/APP695swe cells. Neuronal structural damage in the hippocampal CA1 region of APP/PS1 AD mice was improved according to HE staining and immunohistochemistry of NeuN. Meanwhile, catalpol administration ameliorated cognitive deficits confirmed by behavior performance of APP/PS1 mice. Hoechst 33,342 staining and Annexin V-FITC/PI double staining demonstrated that catalpol could reduce apoptosis in N2a/APP695swe cells. Likewise, TUNEL staining also manifested that catalpol significantly reduced apoptosis in hippocampal CA1 region of APP/PS1 mice. Catalpol administration also could improve mitochondrial functions indicated by the ameliorative mitochondrial morphology, the decreased ROS generation, and the increased MMP in N2a/APP695swe cells. Subsequently, catalpol restrained oligomerization of Aβ1-42, verified by a reduced ThT fluorescence dose- and time-dependently. Additionally, both Aβ1-40 and Aβ1-42 aggregation were decreased in N2a/APP695swe cells and APP/PS1 mice administrated with catalpol confirmed by ELISA and western blot. Western blot also showed that catalpol facilitated the phosphorylation of AKT and GSK3β, and impeded the expression of BACE1 both in vivo and in vitro. Finally, a slight alteration in lactylation, 2-hydroxyisobutyrylation, and phosphorylation were found in N2a/APP695swe cells treated with catalpol. Together, these findings manifested that catalpol served a neuroprotective effect in AD and might be a novel and expecting prophylactic or curative candidate for AD or neurodegenerative diseases therapy.

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Funding

This work was supported by National Natural Science Foundation of Guangdong Province (21202107190000430 and 2022A1515010638), Project of Educational Commission of Guangdong Province (4SG22049G, 4SG22068G, and 4SG22006G), Project of Administration of Traditional Chinese Medicine of Guangdong Province (20222100), Shenzhen Science and Technology Program (JCYJ20210324123211030), GDMU Students’ Innovative Entrepreneurial Training Program (ZZDM002 and ZYDM004), and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation Climbing Program Special Funds (PDJH2022B0222).

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Author notes

  1. Jikun Du, Jierong Liu, Xiaoman Huang, Yuanhua Li, Daibo Song contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China

    Jikun Du, Jierong Liu, Xiaoman Huang, Yuanhua Li, Daibo Song, Qin Li, Jiantao Lin, Baohong Li & Li Li

  2. Central Research Laboratory, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, The Second People’s Hospital of Bao’an Shenzhen (Group) , Shenzhen, China

    Jikun Du

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  1. Jikun Du
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  2. Jierong Liu
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  4. Yuanhua Li
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Correspondence to Jiantao Lin, Baohong Li or Li Li.

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Du, J., Liu, J., Huang, X. et al. Catalpol Ameliorates Neurotoxicity in N2a/APP695swe Cells and APP/PS1 Transgenic Mice. Neurotox Res 40, 961–972 (2022). https://doi.org/10.1007/s12640-022-00524-4

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  • DOI: https://doi.org/10.1007/s12640-022-00524-4

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