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

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.