IGF2BP2 Regulates the Progression of Alzheimer's Disease Through m6A-Mediated NLRP3 Inflammasome

Immun Inflamm Dis. 2025 Jan;13(1):e70121. doi: 10.1002/iid3.70121.

Abstract

Background: Recent studies show that N6-methyladenosine (m6A) plays an important role in the pathogenesis of the Alzheimer's disease (AD), while the mechanisms involved were studied insufficiently.

Aims: The present study aimed to explore the effect of human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2), one of the m6A-binding proteins on the progression of AD.

Materials & methods: The mRNA and protein expression level were determined using RT-qPCR and western blot, respectively. MTT assay was carried out to evaluate cell viability. The content of ROS, antioxidant enzymes, IL-1β and pyroptosis, as well as m6A contents were determined using relative commercial kit. The AD models were built using Aβ1-42 -stimulated hippocampal neuron in vitro and AD mice in vivo.

Results: Our results showed that IGF2BP2 was significantly upregulated in the Aβ1-42 -stimulated hippocampal neuron. IGF2BP2 inhibition reversed the decreased cell viability and the increased cell apoptosis induced by Aβ1-42. IGF2BP2 siRNA transfection alleviated Aβ1-42 induced pyroptosis and pyroptosis-related proteins upregulation. we also found that IGF2BP2 inhibition downregulated the expression of NLRP3 through m6A methylation. Furthermore, overexpression of NLRP3 partly reversed the effect of IGF2BP2 inhibition on Aβ1-42 -induced hippocampal neuron injury. In addition, IGF2BP2 improved cognitive function and alleviated Aβ1-42 neuronal injury in vivo.

Conclusion: Knockdown of IGF2BP2 inhibit neuronal damage and pyroptosis in the hippocampus cells, and improve cognitive function in AD partly through m6A-mediated NLRP3 inflammasome.

Keywords: Alzheimer's disease; Aβ; N6‐methyladenosine; pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine* / analogs & derivatives
  • Adenosine* / metabolism
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Disease Progression
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Inflammasomes* / metabolism
  • Male
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Peptide Fragments / pharmacology
  • Pyroptosis*
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA-Binding Proteins
  • Inflammasomes
  • Amyloid beta-Peptides
  • Adenosine
  • IGF2BP2 protein, human
  • N-methyladenosine
  • Peptide Fragments