Amino Acid Compound 2 (AAC2) Treatment Counteracts Insulin-Induced Synaptic Gene Expression and Seizure-Related Mortality in a Mouse Model of Alzheimer's Disease

Int J Mol Sci. 2024 Oct 30;25(21):11689. doi: 10.3390/ijms252111689.

Abstract

Diabetes is a major risk factor for Alzheimer's disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin's effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2's potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity.

Keywords: Alzheimer’s disease; cognitive; dementia; diabetes; dipeptides; epilepsy; insulin; nanofibers; nanomaterials; seizures; synapses.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal*
  • Gene Expression Regulation / drug effects
  • Insulin* / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Seizures* / chemically induced
  • Seizures* / drug therapy
  • Seizures* / genetics
  • Seizures* / metabolism
  • Synapses / drug effects
  • Synapses / metabolism

Substances

  • Insulin

Grants and funding

The project was supported by Ralph and Marian Falk Medical Research Catalyst Award (J.R.P. and O.Z.), National Science Foundation CHE-2106924 (J.R.P.), and Kathleen Kelly Award (O.Z.). Other supports included NIH grants R21OD017244 (O.Z.), the National Center for Research Resources UL1RR025755 and NCI P30CA16058 (OSUCCC), the NIH Roadmap for Medical Research, Food Innovation Center, Office for International Affairs, and Center for Advanced Functional Foods Research and Entrepreneurship at OSU (O.Z.). The content is solely the responsibility of the authors and does not represent the official views of the National Center for Research Resources or the NIH.