Insulin Inhibits Aβ42 Aggregation and Prevents Aβ42-Induced Membrane Disruption

Biochemistry. 2019 Nov 12;58(45):4519-4529. doi: 10.1021/acs.biochem.9b00696. Epub 2019 Nov 4.

Abstract

Alzheimer's disease (AD) is associated with self-assembly of amyloid β-protein (Aβ) into soluble oligomers. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is particularly strongly linked to AD. Longitudinal studies revealed a correlation between AD and type 2 diabetes (T2D), characterized by abnormal insulin levels and insulin resistance. Although administration of intranasal insulin is explored as a therapy against AD, the extent to which insulin affects Aβ dynamics and activity is unclear. We here investigate the effect of insulin on Aβ42 self-assembly and characterize the capacity of insulin, Aβ42, and Aβ42 co-incubated with insulin to disrupt the integrity of biomimetic lipid vesicles. We demonstrate that quiescently incubated insulin, which does not form amyloid fibrils, over time develops membrane-disrupting capacity, which we propose to originate in misfolded insulin monomers. These hypothetically toxic misfolded monomers might contribute to the development of insulin resistance in early stages of T2D that are associated with abnormally high insulin levels. We show that in contrast to quiescent incubation, insulin incubated under agitated conditions readily forms amyloid fibrils, which protect against membrane permeation. Insulin quiescently incubated with Aβ42 attenuates both Aβ42 fibril formation and the ability of Aβ42 to disrupt membranes in a concentration-dependent manner. Our findings offer insights into interactions between insulin and Aβ42 that are relevant to understanding the molecular basis of intranasal insulin as a therapy against Aβ-induced AD pathology, thereby elucidating a plausible mechanism underlying the observed correlations between AD and T2D.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Insulin / metabolism*
  • Insulin / pharmacology*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / ultrastructure
  • Protein Aggregates / drug effects
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism

Substances

  • Amyloid beta-Peptides
  • Insulin
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)