Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive dysfunction

Abstract

BackgroundInsulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive impairment, but its mechanism is not fully clari ed. The aim of the study was to reveal whether IGF-1 treated cognitive impairment by improving tau pathology and neuronal pyroptosis in high-fat diet mice, and to further explore its molecular mechanisms involved. MethodsDuring in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations. Cognitive function was evaluated using Morris water maze. Expression of Nrf-2, HO-1, p-tau, NLRP3, Caspase-1 and IL-1β in hippocampus was determined using western blotting. Pyroptosis rate in hippocampus was measured using ow cytometry. During in vivo experiment, HN-h cells were treated with palmic acid, pyroptosis blocker nonecrosulfonamide or their combinations. The expression of the proteins and pyroptosis rate were also measured using western blotting and ow cytometry. ResultsDuring in vitro experiment, high-fat diet mice showed cognitive impairment, hyperphospharylation of tau protein and signi cant neuronal pyroptosis in hippocampus compared with the sham mice. After exogenous IGF-1 treatment, these abnormalities were reversed, and Nrf-2/HO-1 signaling pathway was activated. Inhibition of such signaling pathway using IGF-1 receptor blocker or HO-1 blocker redeteriorated cognitive function, neuronal pyroptosis and tau pathology in hippocampus. During in vivo experiment, inhibition of pyroptosis using its blocker improved tau pathology in palmic acid-treated HN-h cells. ConclusionExogenous IGF-1 improved cognitive impairment, tau pathology and neuronal pyroptosis induced by highfat diet through activation of Nrf-2/HO-1 signaling pathway.

C1q/tumor necrosis factor (TNF)-associated protein 6 (CTRP6) ameliorates the cognitive dysfunction induced by sevoflurane by activating AMPK/SIRT1 pathway in rats

“…POCD is potentially involved in central nervous, endocrine, and immune systems disorders, but its mechanism is still unclear [12]. To improve the outcome of POCD, we aimed to clarify the regulatory mechanism and identify key regulatory proteins.…”

Insulin-like growth factor 1 in heat stress-induced neuroinflammation: novel perspective about the neuroprotective role of chromium

“…According to Wang et al, IGF-1 protects SH-SY5Y cells against Aβ-induced cell injury by reducing ROS through the PI3K/Akt-Nrf2 signaling pathway in an AD model (Wang et al 2017 ). Similarly, Sui et al reported that IGF-1 improved tau pathology induced by high-fat diet via the activation of the Nrf2/HO-1 signaling pathway (Sui et al 2021 ). Moreover, knockdown of IGF-1 was shown to reduce antioxidant defenses by impairing the Nrf2-dependent antioxidant response (Bailey-Downs et al 2012 ).…”

The role of pyroptosis in cognitive impairment

“…Sui et al reported that under HFD conditions, neuronal pyroptosis was significantly increased, tau protein was hyperphosphorylated, Nrf-2/ HO-1 signaling pathway was activated. Exogenous IGF-1 could improve cognitive impairment in a C57BL/6 J mice model fed with HFD by reversing the activity of the above signaling (Sui et al, 2021). MicroRNAs also showed potential in treating obesity/HFD-related cognitive impairment.…”