Over‐expression of N‐acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse

• Published in: Journal of neurochemistry 2024-02, Vol.168 (2), p.69-82
• Main Authors: Francis, Jeremy S., Nguyen, Quy, Markov, Vladimir, Leone, Paola
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Adenosine Triphosphate - metabolism; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino acids; Animals; Aspartic Acid - metabolism; ATP; Bioavailability; Biomarkers; Central nervous system; Cognitive ability; Cognitive Dysfunction; Energy metabolism; metabolic decline; Mice; Mitochondria; Neurodegenerative disease; Neurodegenerative diseases; N‐acetylaspartate; Oxidative phosphorylation; Phosphorylation; Substrates; Synthesis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.16044

N‐acetylaspartate (NAA) is an abundant central nervous system amino acid derivative that is tightly coupled to mitochondria and energy metabolism in neurons. A reduced NAA signature is a prominent early pathological biomarker in multiple neurodegenerative diseases and becomes progressively more pronounced as disease advances. Because NAA synthesis requires aspartate drawn directly from mitochondria, we argued that this process is in direct competition with oxidative phosphorylation for substrate and that sustained high levels of NAA synthesis would be incompatible with pathological energy crisis. We show here that over‐expression of the rate‐limiting NAA synthetic enzyme in the hippocampus of the 5x familial Alzheimer's disease (5xFAD) mouse results in an exaggerated pathological ATP deficit and accelerated cognitive decline. Over‐expression of NAA synthase did not increase amyloid burden or result in cell loss but did significantly deplete mitochondrial aspartate and impair the ability of mitochondria to oxidize glutamate for adenosine triphosphate (ATP) synthesis. These results define NAA as a sink for energetic substrate and suggest initial pathological reductions in NAA are part of a response to energetic crisis designed to preserve substrate bioavailability for mitochondrial ATP synthesis. Increasing NAA synthase (Nat8L) via AAV‐mediated overexpression in a model of Alzheimer’s Disease compromises mitochondrial energy metabolism. Sequestration of mitochondrial aspartate by NAA is incompatible with pathological energetic crisis, accelerates associated cognitive decline and presents a rationale for the active reduction of NAA in a broad clinical spectrum of neurodegenerative disease. Image content: Overexpression of NAA synthase (Nat8L) in hippocampal Neurons of 5xFAD mice compounds phenotypic energy deficit and accelerates cognitive decline. Cover image for this issue: https://doi.org/10.1111/jnc.15854