The Impact of the hAPP695SWTransgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways

Mona Khorani, Gerd Bobe, Donald G. Matthews, Armando Alcazar Magana, Maya Caruso, Nora E. Gray, Joseph F. Quinn, Jan F. Stevens, Amala Soumyanath, Claudia S. Maier

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: To gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.

Original languageEnglish (US)
Pages (from-to)1601-1619
Number of pages19
JournalJournal of Alzheimer's Disease
Volume85
Issue number4
DOIs
StatePublished - 2022

Keywords

  • Alzheimer's disease
  • Tg2576
  • excitatory and inhibitory imbalance
  • fatty acids
  • hAPP695
  • hippocampus
  • metabolomics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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