title: Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca²⁺ dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood. We found that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca²⁺ handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca²⁺ dysregulation caused an impairment of post-tetanic potentiation in mossy fiber-CA3 synapses. The alteration of cellular Ca²⁺ clearance in Tg2576 mice is region-specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca²⁺ clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca²⁺ uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes.
authors.affiliation: Cell Physiology Laboratory, Department of Physiology and bioMembrane Plasticity Research Center, Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Kim
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Ryu
authors.forename: Sungmin
authors.initials: S
authors.lastname: Son
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: Suk-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Ho
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000473:pathology*; D019599:Mossy Fibers, Hippocampal / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017975:Ruthenium Compounds / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D002839:Chromans; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C112020:Ru 360; D017975:Ruthenium Compounds; D019831:Sodium-Calcium Exchanger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium