TitleThe Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways.
Publication TypeJournal Article
Year of Publication2022
AuthorsKhorani M, Bobe G, Matthews DG, Magana AAlcazar, Caruso M, Gray NE, Quinn JF, Stevens JF, Soumyanath A, Maier CS
JournalJ Alzheimers Dis
Date Published2022
KeywordsAged, Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Disease Models, Animal, Female, Hippocampus, Humans, Metabolomics, Mice, Mice, Transgenic, Signal Transduction, Transgenes

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.

Alternate JournalJ Alzheimers Dis
PubMed ID34958022
PubMed Central IDPMC9584213
Grant ListI01 BX003440 / BX / BLRD VA / United States
U19 AT010829 / AT / NCCIH NIH HHS / United States
R01 AT008099 / AT / NCCIH NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States
T32 AT002688 / AT / NCCIH NIH HHS / United States