HIF-1α is a “brake” in JNK-mediated activation of amyloid protein precursor and hyperphosphorylation of tau induced by T-2 toxin in BV2 cells

Abstract

Mycotoxins have the capacity of triggering neurodegenerative conditions like Alzheimer's disease (AD), which is marked by β-amyloid (Aβ) deposition and hyperphosphorylation of tau (P-tau). However, there is no evidence of an exact molecular mechanism to prove the above point. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters amyloid precursor protein (APP) and P-tau formation in BV2 cells, and determined the underlying roles of HIF-1α and JNK3 signaling. The ndings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a "brake" on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK3 signaling, which broke this "brake" to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK3/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK3 might interfere with HIF-1α's protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins.

The relationship between hypoxia and Alzheimer’s disease: an updated review

“…In Zhao et al’s (2024) study, they found the level of hyperphosphorylated tau induced by T-2 toxin increased when HIF-α signaling was inhibited. This suggested that HIF-1α played a protective role in the T-2 toxin-induced expression of hyperphosphorylated tau ( Zhao et al, 2024 ). Taken together, we have sufficient reasons to believe that HIF-1α is associated with tau pathology in AD, however, the specific mechanism remains unclear and requires further research.…”

“…After entering the brain, T-2 toxin can cause further damage by triggering oxidative stress, neuroinflammation, and even apoptosis and it can also induce the rise of phosphorylated tau protein. A study has found that T-2 toxin can induce the expression of hyperphosphorylated tau ( Zhao et al, 2024 ). In Zhao et al’s (2024) study, they found the level of hyperphosphorylated tau induced by T-2 toxin increased when HIF-α signaling was inhibited.…”

“…A study has found that T-2 toxin can induce the expression of hyperphosphorylated tau ( Zhao et al, 2024 ). In Zhao et al’s (2024) study, they found the level of hyperphosphorylated tau induced by T-2 toxin increased when HIF-α signaling was inhibited. This suggested that HIF-1α played a protective role in the T-2 toxin-induced expression of hyperphosphorylated tau ( Zhao et al, 2024 ).…”