TRPV1 Modulator Ameliorates Alzheimer-Like Amyloid-β Neuropathology via Akt/Gsk3β-Mediated Nrf2 Activation in the Neuro-2a/APP Cell Model

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.

Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice

“…AKT1 phosphorylation (pAKT1) was significantly increased (P < 0.01) in the organ of Corti lysates from animals cotreated with kanamycin and PL compared with the rest of the groups. These results are in accordance with previous studies showing the protective effect of AKT activation against neurodegenerative disorders (35) and the modulation of AKT's activity by PL (23).…”

“…Thus, the constant binding of PL to TRPV1's allosteric site may have a twofold effect; initially, it blocks activity, but, eventually, it will decrease surface expression. The link between TRPV1 activation and AKT1 inhibition has previously been shown (35). In the present work, we found that (i) pAKT1 is reduced during kanamycin treatment (kinome, immunohistochemistry, and immunoblot assays) and (ii) treatment with PL or absence of TRPV1 results in a modest, but significant (P < 0.05), activation of AKT1.…”

“…This increment in TRPV1 results in an exacerbation of AG ototoxicity because of an increase in AG uptake, with TRPV1 playing a key role during this process (39). In addition, TRPV1 activation can affect mitochondrial homeostasis and reactive oxygen species production by preventing AKT activation (35). More importantly and directly related to the present work, a recently published study has demonstrated that PL can allosterically antagonize TRPV channel activity (18).…”

Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3β-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model

“…Apart from being as a kinase involved in tau phosphorylation and the production of A␤ [56,57], GSK-3␤ has a role in keeping homeostasis of neural progenitor in the rodent brains during the early developmental period [58]. In our preceding scholarly publication, the impact of GSK-3 activation or inhibition on neurogenesis was examined [59,60].…”