Targeting IGF2BP2 alleviates high fat diet aggravated Alzheimer's disease by inhibiting ferroptosis.

Abstract

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose development is increasingly recognized to be influenced by metabolic factors such as high-fat diet (HFD). HFD can accelerate cognitive decline and exacerbate AD pathology by promoting oxidative stress, neuroinflammation, and lipid dysregulation. Meanwhile, ferroptosis-an iron-dependent form of regulated cell death-has emerged as a key mechanism contributing to neuronal damage in AD. However, the upstream regulators that link HFD-induced stress to ferroptosis and AD progression remain unclear. IGF2BP2, an m⁶A RNA-binding protein, has been implicated in both metabolic regulation and mRNA stability, but its role in AD under HFD conditions has not been fully elucidated. METHODS: We established AD models both in vivo and in vitro and subjected them to HFD exposure. Behavioral and biochemical assessments-including Morris water maze, H&E staining, serum triglyceride (TG) and total cholesterol (TC) levels, and ELISA for Aβ and m6A-were conducted. Transcriptomic sequencing identified IGF2BP2 as a differentially expressed gene associated with AD progression under HFD. IGF2BP2 expression was silenced using siRNA in cells and adeno-associated virus (AAV) in rats. Apoptosis, Aβ, TNF-α, IL-1β, and m6A levels were evaluated post-knockdown. Ferroptosis markers (ROS, SOD, GSH, MDA, and SLC7A11) and mitochondrial ultrastructure were also assessed. RESULTS: HFD exacerbated cognitive dysfunction, neuronal damage, lipid metabolism disorder, Aβ accumulation, and m6A hypomodification in AD models. IGF2BP2 expression was significantly elevated in HFD-induced AD, and its knockdown alleviated neuroinflammation, apoptosis, and restored m6A modification. Notably, silencing IGF2BP2 enhanced SLC7A11 expression and reduced ferroptosis-related oxidative stress, mimicking the effects of the ferroptosis inhibitor Fer-1. Moreover, IGF2BP2 knockdown lowered serum TG and TC levels and improved cognitive performance in the Morris water maze. CONCLUSION: Our findings identify IGF2BP2 as a key mediator linking HFD-induced metabolic dysfunction to AD progression via m6A modification and ferroptosis. Targeting IGF2BP2 may represent a promising therapeutic strategy for AD patients with metabolic comorbidities.