title: Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease.
abstract: BACKGROUND
  The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.
  
  
  RESULTS
  We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.
  
  
  CONCLUSIONS
  Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Neurology, Mayo Clinic, Rochester, Minnesota, United States of America. Trushina.eugenia@mayo.edu
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.forename: Emirhan
authors.initials: E
authors.lastname: Nemutlu
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: Trace
authors.initials: T
authors.lastname: Christensen
authors.forename: Jon
authors.initials: J
authors.lastname: Camp
authors.forename: Janny
authors.initials: J
authors.lastname: Mesa
authors.forename: Ammar
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wengenack
authors.forename: Petras P
authors.initials: PP
authors.lastname: Dzeja
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000682:Amyloid / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D013997:Time Factors
chemical_list: D000682:Amyloid; D015415:Biomarkers; D053764:Presenilin-1