The pLG72-DAAO Pathway Regulates D-Amino Acids in the Central Nervous System, and Protects Against Neurodegenerative Disorders such as Alzheimer’s Dementia
Cortland Baum
Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that presents in individuals with gradual cognitive decline.1 Its prevalence has increased 148% from 2000 to 2018 and it is estimated to have totaled $305 billion in healthcare costs globally in 2020.2 Currently diagnosis of the disease is based on behavioral patterns of the patient and medical history and treatment is limited to acetylcholinesterase inhibitors and NMDA antagonists.1,6 D-serine is known to play an important role in the stimulation of the NMDA receptor. Dysregulation of the processes that regulate D-serine are associated with triggering various disease states such as AD and schizophrenia.2,3,4 Levels of D-serine in the human brain are regulated by two enzymes, serine racemase (SR) and D-amino acid oxidase (DAAO). SR synthesizes D-serine while DAAO is a protein that degrades D amino-acids.2
Objective: In this review, assessment of methods to diagnose Alzheimer’s development earlier than currently possible as well as ways to pharmacologically modulate levels of D-amino acids in the CNS were explored.
Search Methods: An online search in the PubMed database was conducted from 2018-2024 using the following keywords: “Alzheimers Dementia”, “DAAO” and “NMDA”.
Results: The structure of DAAO is known, and the amino acid position R120 is significant because it is the active site where FAD interacts with it to form an active holoenzyme.3 R120E and R120L variants of DAAO resulted in an enzyme with higher efficiency as compared to wild types.3 Tak-831 (Luvadaxistat) is is a newly synthesized compound 4-hydroxy-6-[21]-pyridazine-3(2H)-1 that is thought to be a DAAO inhibitor and hence lead to increased stimulation of the NMDA receptor.5 In an experiment where the drug was administered to mice, D-serine was increased in the plasma, CSG and cerebellum as compared to the control rats that did not take Luvadaxistat.5 Evaluation of patients with Alzheimer’s dementia (AD) as compared to unaffected individuals with Western Blotting shows that AD patients have an statistically significantly increased level of pLG72 as compared to the control group of individuals showing no signs or symptoms of AD.1 Evaluation of the levels of pLG72 in the different stages of dementia showed a non linear progression. Early to middle stage AD showed increased levels of pLG72 while late stages of AD showed relatively decreased levels.4 Using fMRI different regions of the brain can be evaluated for changes in regional homogeneity (ReHo). ReHo changes are used to assess functional connectivity of a brain region to the rest of the brain.6 MCI patients given sodium benzoate as compared to a control group showed decreased ReHo in the right middle frontal gyrus. Furthermore this change in ReHo was positively correlated with working memory in the benzoate group.6
Conclusions: These studies show that D-amino acids in the CNS can be altered using drugs that act on the DAAO pathway. Future work can assess how modulating D-amino acids levels in CSF could in turn regulate NMDA receptor stimulation.
Works cited:
- Lane HY, Lin CH. Diagnosing Alzheimer’s Disease Specifically and Sensitively With pLG72 and Cystine/Glutamate Antiporter SLC7A11 AS Blood Biomarkers. Int J Neuropsychopharmacol. 2023;26(1):1-8. doi:10.1093/ijnp/pyac053
- Takagi S, Balu DT, Coyle JT. Factors regulating serine racemase and d-amino acid oxidase expression in the mouse striatum. Brain Res. 2021;1751:147202. doi:10.1016/j.brainres.2020.147202
- Murtas G, Sacchi S, Pollegioni L. Substitution of Arginine 120 in Human D-Amino Acid Oxidase Favors FAD-Binding and Nuclear Mistargeting. Front Mol Biosci. 2019;6:125. Published 2019 Nov 12. doi:10.3389/fmolb.2019.00125
- Lin CH, Chiu CC, Huang CH, Yang HT, Lane HY. pLG72 levels increase in early phase of Alzheimer’s disease but decrease in late phase. Sci Rep. 2019;9(1):13221. Published 2019 Sep 13. doi:10.1038/s41598-019-49522-1
- Fradley R, Goetghebeur P, Miller D, et al. Luvadaxistat: A Novel Potent and Selective D-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia [published correction appears in Neurochem Res. 2023 Jul 13;:]. Neurochem Res. 2023;48(10):3027-3041. doi:10.1007/s11064-023-03956-2
- Lane HY, Tu CH, Lin WC, Lin CH. Brain Activity of Benzoate, a D-Amino Acid Oxidase Inhibitor, in Patients With Mild Cognitive Impairment in a Randomized, Double-Blind, Placebo Controlled Clinical Trial. Int J Neuropsychopharmacol. 2021;24(5):392-399. doi:10.1093/ijnp/pyab001