Scorpion venom heat-resistant synthetic peptide regulates Nrf-2 to alleviate neuronal pyroptosis in an AD model induced by endoplasmic reticulum stress under PM2.5 exposure

In recent years, the impact of fine particulate matter (PM_2.5) on the nervous system, particularly on neurodegenerative diseases, has garnered widespread attention. Epidemiological studies have shown that exposure to PM_2.5 is closely associated with the development and progression of Alzheimer's disease (AD). However, the mechanisms through which PM_2.5 exacerbates AD remain unclear. Scorpion venom heat-resistant synthetic peptide (SVHRSP) is a pharmacologically active product synthesised from the amino acid sequence of scorpion venom heat-resistant peptide. In this study, we investigated the mechanism through which PM_2.5 exposure aggravates neuronal pyroptosis and validated the protective effects of SVHRSP against AD. PC12 and HT22 neuronal cells were used to construct in vitro models of AD. Mice were stereotactically injected with Aβ_25-35 protein to induce AD. Subsequently, PM_2.5 exposure-induced changes in ER stress, pyroptosis, and oxidative stress in AD models, were detected through in vivo and in vitro experiments. The results indicated that PM_2.5 exposure aggravated cognitive impairment, ER stress, and pyroptosis in mice with AD. Conversely, treatment with SVHRSP counteracted the damage induced by PM_2.5 exposure. At a mechanistic level, PM_2.5 might enhance oxidative stress and trigger pyroptosis by suppressing the expression of Nrf-2. These findings offer novel insights into the mechanisms through which PM_2.5 exposure hastens the progression of AD and propose a promising strategy for the pharmacological treatment of AD.