TRPV1 Modulator Ameliorates Alzheimer-Like Amyloid- β Neuropathology via Akt/Gsk3 β-Mediated Nrf2 Activation in the Neuro-2a/APP Cell Model

  • Oxid Med Cell Longev. 2022 Aug 27:2022:1544244. doi: 10.1155/2022/1544244.
Xiufen Wang  1 ,  Yaqi Bian  1  2 ,  Clarence Tsun Ting Wong  3 ,  Jia-Hong Lu  1 ,  Simon Ming-Yuen Lee  1  4
Affiliations
  • 1. State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 2. Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China.
  • 3. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 4. Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao, China.
PMID: 36065437 DOI: 10.1155/2022/1544244
Abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder for which there is no effective therapeutic strategy. PcActx peptide from the transcriptome of zoantharian Palythoa caribaeorum has recently been identified and verified as a novel antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). In the present study, we further investigated the neuroprotective potential of PcActx peptide and its underlying mechanism of action, in an N2a/APP cell model of AD. Both Western blot and RT-PCR analysis revealed that PcActx peptide markedly inhibited the production of amyloid-related proteins and the expression of BACE1, PSEN1, and PSEN2. Moreover, PcActx peptide notably attenuated the capsaicin-stimulated calcium response and prevented the phosphorylation of CaMKII and CaMKIV (calcium-mediated proteins) in N2a/APP cells. Further investigation indicated that PcActx peptide significantly suppressed ROS generation through Nrf2 activation, followed by enhanced NQO1 and HO-1 levels. In addition, PcActx peptide remarkably improved Akt phosphorylation at Ser 473 (active) and Gsk3β phosphorylation at Ser 9 (inactive), while pharmacological inhibition of the Akt/Gsk3β pathway significantly attenuated PcActx-induced Nrf2 activation and amyloid downregulation. In conclusion, PcActx peptide functions as a TRPV1 modulator of intercellular calcium homeostasis, prevents AD-like amyloid neuropathology via Akt/Gsk3β-mediated Nrf2 activation, and shows promise as an alternative therapeutic agent for AD.

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