title: Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis.
abstract: Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo (1)H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysis enzymes pyruvate dehydrogenase kinase and lactate dehydrogenase A within cortical and hippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD.
  
  
  CONCLUSIONS
  Lactate has recently emerged as a key metabolite necessary for memory consolidation. Lactate is the end product of aerobic glycolysis, a unique form of metabolism that occurs within certain regions of the brain. Here we detected an age-dependent decline in the expression of aerobic glycolysis enzymes and a concomitant decrease in lactate levels within the frontal cortex of wild-type mice. Improved memory performance in wild-type mice correlated with elevated expression of aerobic glycolysis enzymes. Surprisingly, lactate levels remained elevated with age and increased aerobic glycolysis enzyme expression correlated with poorer memory performance in APP/PS1 mice. These findings suggest that while lactate production is beneficial for memory in the healthy aging brain, it might be detrimental in an Alzheimer's disease context.
authors: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors: Richard A
authors: RA
authors: Harris
authors: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors: Lauren
authors: L
authors: Tindale
authors: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors: Asad
authors: A
authors: Lone
authors: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors: Olivia
authors: O
authors: Singh
authors: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors: Shannon L
authors: SL
authors: Macauley
authors: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors: Molly
authors: M
authors: Stanley
authors: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors: David M
authors: DM
authors: Holtzman
authors: Department of Physiology and Pharmacology, University of Western Ontario, and Molecular Brain Research Group, Robarts Research Institute, London, Ontario N6A 5B7, Canada.
authors: Robert
authors: R
authors: Bartha
authors: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada, rcummin5@uwo.ca.
authors: Robert C
authors: RC
authors: Cumming
mesh_terms: D000332:Aerobiosis / Q000502:physiology; D000375:Aging / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D005625:Frontal Lobe / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008568:Memory / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D027501:Monocarboxylic Acid Transporters; D053764:Presenilin-1; C580804:presenilin 1, mouse; D019344:Lactic Acid
keywords: Alzheimer's disease; aerobic glycolysis; amyloid; lactate; magnetic resonance spectroscopy; memory