Mona Khorani1, Gerd Bobe2, Donald G Matthews3, Armando Alcazar Magana1,2, Maya Caruso3, Nora E Gray3, Joseph F Quinn3,4, Jan F Stevens2,5, Amala Soumyanath3, Claudia S Maier1,2. 1. Department of Chemistry, Oregon State University, Corvallis, OR, USA. 2. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA. 3. Department of Neurology, Oregon Health & Science University, Portland, OR, USA. 4. Parkinson's Disease Research Education and Clinical Care Center, Veterans' Administration Portland Health Care System, Portland, OR, USA. 5. Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA.
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.
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.
Authors: Marcus A Westerman; Deirdre Cooper-Blacketer; Ami Mariash; Linda Kotilinek; Takeshi Kawarabayashi; Linda H Younkin; George A Carlson; Steven G Younkin; Karen H Ashe Journal: J Neurosci Date: 2002-03-01 Impact factor: 6.167
Authors: Cécile Bascoul-Colombo; Irina A Guschina; Benjamin H Maskrey; Mark Good; Valerie B O'Donnell; John L Harwood Journal: Biochim Biophys Acta Date: 2016-03-09