title: AβPP-Transgenic 2576 Mice Mimic Cell Type-Specific Aspects of Acetyl-CoA-Linked Metabolic Deficits in Alzheimer's Disease.
abstract: The pyruvate-derived acetyl-CoA is a principal direct precursor substrate for bulk energy synthesis in the brain. Deficits of pyruvate dehydrogenase in the neocortex are common features of Alzheimer's disease and other age-related encephalopathies in humans. Therefore, amyloid-β overload in brains of diverse transgenic Alzheimer's disease model animals was investigated as one of neurotoxic compounds responsible for pyruvate dehydrogenase inhibition yielding deficits of cholinergic neurotransmission and cognitive functions. Brains of aged, 14-16-month-old Tg2576 mice contained 0.6 μmol/kg levels of amyloid-β1 - 42. Activities of pyruvate dehydrogenase complex, choline acetyltransferase, and several enzymes of acetyl-CoA and energy metabolism were found to be unchanged in both forebrain mitochondria and synaptosomes of Tg2576 mice, indicating preservation of structural integrity at least in cholinergic neuronal cells. However, in transgenic brain synaptosomes, pyruvate utilization, mitochondrial levels, and cytoplasmic acetyl-CoA levels, as well as acetylcholine content and its quantal release, were all found to be decreased by 25-40% . On the contrary, activation of pyruvate utilization was detected and no alterations in acetyl-CoA content and citrate or α-ketoglutarate accumulation were observed in transgenic whole brain mitochondria. These data indicate that amyloid-β evoked deficits in acetyl-CoA are confined to mitochondrial and cytoplasmic compartments of Tg2576 nerve terminals, becoming early primary signals paving the path for further stages of neurodegeneration. On the other hand, acetyl-CoA synthesis in mitochondrial compartments of glial cells seems to be activated despite amyloid-β accumulated in transgenic brains.
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bielarczyk
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jankowska-Kulawy
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Höfling
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ronowska
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Gul-Hinc
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Roßner
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schliebs
authors.affiliation: Department of Molecular Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pawelczyk
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szutowicz
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019343:Citric Acid / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007656:Ketoglutaric Acids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019343:Citric Acid; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D000109:Acetylcholine
keywords: Acetylcholine; Tg2576 mice; acetyl-CoA; amyloid-β; choline acetyltransferase; pyruvate dehydrogenase; synaptosomes; whole brain mitochondria