The Impact of the hAPP695^SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways

Article type: Research Article

Authors: Khorani, Mona^{a; 1} | Bobe, Gerd^{b; 1} | Matthews, Donald G.^{c; 1} | Magana, Armando Alcazar^{a; b} | Caruso, Maya^c | Gray, Nora E.^c | Quinn, Joseph F.^{c; e} | Stevens, Jan F.^{b; d} | Soumyanath, Amala^{c; *} | Maier, Claudia S.^{a; b; *}

Affiliations: [a] Department of Chemistry, Oregon State University, Corvallis, OR, USA | [b] Linus Pauling Institute, Oregon State University, Corvallis, OR, USA | [c] Department of Neurology, Oregon Health & Science University, Portland, OR, USA | [d] Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA | [e] Parkinson’s Disease Research Education and Clinical Care Center, Veterans’ Administration Portland Health Care System, Portland, OR, USA

Correspondence: [*] Correspondence to: Amala Soumyanath, Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Tel.: +1 503 494 6878; E-mail: [email protected] and Claudia S. Maier, Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331, USA. Tel.: +1 541 737 9533; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, excitatory and inhibitory imbalance, fatty acids, hAPP695^SW , hippocampus, metabolomics, Tg2576

DOI: 10.3233/JAD-215084

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1601-1619, 2022