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-catabolising 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 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.

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

“…While lower NAA levels in neurodegenerative diseases may be a marker of neuronal loss, they may also reflect compromised NAA synthesis within neurons facing increasing bioenergetic demand due to perturbations in mitochondrial oxidative phosphorylation. In this context, it is interesting to note that Zaroff and colleagues recently reported under-expression of NAT8L as well as NAA levels in a transgenic mouse model of AD, even in the absence of significant neuronal loss [81]. Our findings are in broad agreement with those of Paglia and colleagues who showed evidence for dysregulation in brain aspartate and glutamate metabolism in AD [46].…”

“…Consistent with numerous prior studies using 1 H-MRS that have shown lower levels of NAA in AD within regions vulnerable to pathology, such as the posterior cingulate cortex and hippocampus [51], our CE-MS assays also showed evidence of lower NAA concentration in the ITG in AD as well as associations with lower concentrations and more severe amyloid pathology and neurofibrillary pathology. Besides being a well-recognized neuroimaging marker of neuronal metabolic integrity, NAA plays several important biological roles including in myelin turnover, mitochondrial energy production, neuronal osmoregulation, and neuron-glia signaling [79][80][81]. Its synthesis within neurons occurs in an energy-dependent reaction that is catalyzed by neuron-specific N-acetyltransferase (NAT8L) (Fig 8), utilizing glutamate as a transamination source for aspartate and either pyruvate or 3-hydroxybutyrate as a source of acetyl CoA [80].…”

The Impact of Acetyl-CoA and Aspartate Shortages on the N-Acetylaspartate Level in Different Models of Cholinergic Neurons

“…Our previous project revealed that the reduction of the NAA level is strongly associated with acetyl-CoA shortages as well as with the inhibition of NAT8L activity and NAT8L protein content [ 4 ]. This is consistent with our findings in the present project ( Table 4 ), although in this study we also considered disturbances in the malate–aspartate shuttle as affecting NAA synthesis, as other researchers have suggested [ 52 , 53 , 54 ]. Two crucial MAS enzymes, malate dehydrogenase (MDH) and aspartate aminotransferase, seem to be resistant to 0.15 mM Zn 2+ -dependent inhibition, which is consistent with the findings reported by other researchers as well [ 55 , 56 ].…”

Molecular differences in Alzheimer's disease between male and female patients determined by integrative network analysis

“…NAA is abundant in the brain, and its hydrolysis by ASPA is thought to contribute to the maintenance of white matter . NAA levels were found to be abnormal during early AD in a mouse model, which was associated with deficits in mitochondrial oxidative phosphorylation . ESRRB is a protein with similarity to the receptor of oestrogen, which regulates key processes in AD pathogenesis and underlies sex differences in AD .…”