title: Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.
abstract: N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system. Downreguation of Nat8L is particularly pronounced in the 5xFAD hippocampus, and is preceded by a significant upregulation of oligodendrocytic aspartoacylase (aspa), which encodes for the sole known NAA-catabolizing enzyme in the brain. Reductions in 5xFAD NAA and Nat8L cannot be accounted for by discrepancies in either neuron content or activity of the substrate-providing malate-aspartate shuttle, thereby implicating transcriptional regulation in a coordinated response to pathological energetic crisis. A central role for ASPA in this response is supported by a parallel developmental analysis showing highly significant increases in Nat8L expression in an ASPA-null mouse model during a period of early postnatal development normally punctuated by the transcriptional upregulation of aspa. These results provide preliminary evidence of a signaling mechanism in Alzheimer's disease that involves cross talk between neurons and oligodendrocytes, and suggest that ASPA acts to negatively regulate Nat8L expression. This mechanism is proposed to be a fundamental means by which the brain conserves available substrate during energy crises.
authors.affiliation: Cell & Gene Therapy Centre, Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA; Graduate School of Biomedical Sciences, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Zaroff
authors.affiliation: Cell & Gene Therapy Centre, Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Leone
authors.affiliation: Cell & Gene Therapy Centre, Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Markov
authors.affiliation: Cell & Gene Therapy Centre, Department of Cell Biology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA. Electronic address: francijs@rowan.edu.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Francis
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D000123:Acetyltransferases; C521704:Shati protein, mouse; D000581:Amidohydrolases; C019751:aspartoacylase
keywords: Alzheimer's Disease; N-acetylaspartate; Oligodendrocyte; Transcriptional regulation; energetic crisis