Newfound effect of N-acetylaspartate in preventing and reversing aggregation of amyloid-beta in vitro

Abstract

Although N-acetylaspartate (NAA) has long been recognized as the most abundant amino acid in neurons by far, its primary role has remained a mystery. Based on its unique tertiary structure, we explored the potential of NAA to modulate aggregation of amyloid-beta (Aβ) peptide 1-42 via multiple corroborating aggregation assays along with electron microscopy. Thioflavin-T fluorescence assay demonstrated that at physiological concentrations, NAA substantially inhibited the initiation of Aβ fibril formation. In addition, NAA added after 25 min of Aβ aggregation was shown to break up preformed fibrils. Electron microscopy analysis confirmed the absence of mature fibrils following NAA treatment. Furthermore, fluorescence correlation spectroscopy and dynamic light scattering measurements confirmed significant reductions in Aβ fibril hydrodynamic radius following treatment with NAA. These results suggest that physiological levels of NAA could play an important role in controlling Aβ aggregation in vivo where they are both found in the same neuronal compartments.

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: A multimodal fMRI and 1H‐MRS study

“…Levels of tNAA have been shown to be highly heritable (Batouli et al, ), but are also sensitive to early environmental influences, including stress (McLean et al, ). Future large scale studies of genetic and environmental influences on PCu/PCC metabolite levels in humans across the lifespan will be required to address this critical question, which may have implications for understanding lifespan influences on cognitive and neural ageing (Dollé et al, ; Jagust & Mormino, ).…”

“…Our findings also suggest some regional specificity of the link between BOLD and tNAA, since we found no correlation between OCC tNAA and the OCC response to scenes. This could reflect some unique physiological properties of PCu/PCC and/or tNAA (Dollé et al, ). NAA is not distributed homogeneously in the brain, but rather, levels are highly variable among different neuronal types (Moffet et al, ).…”

Longitudinal MRI findings in patient with SLC25A12 pathogenic variants inform disease progression and classification

“…NAA is transported to glial cells, particularly oligodendrocytes, where it is likely used for lipid and myelin synthesis (Burri, Steffen, & Herschkowitz, ; Chakraborty, Mekala, Yahya, Wu, & Ledeen, ; Francis et al, ; Moffett, Ross, Arun, Madhavarao, & Namboodiri, ), although an absence of NAA does not preclude myelin formation (Martin, Capone, Schneider, Hennig, & Thiel, ). NAA is also potentially involved in osmoregulation (Baslow, ), nitrogen balance (Moffett et al, ), and the inhibition of protein aggregation (Dolle et al, ).…”

Brain Metabolite, N-Acetylaspartate Is a Potent Protein Aggregation Inhibitor

“…Our results indicate that in the presence of NAA, Aβ or alphasynuclein aggregation should be prevented. In support, it has been reported that NAA suppresses the aggregation of Aβ42 (Dollé et al, 2018). Thus, it appears that increase in the Aβ or alpha synuclein aggregation under the pathologic conditions, is due to decrease in the NAA concentration making it insufficient to modulate aggregation pathway.…”