The Role of D-Amino Acids in Alzheimer’s Disease

2021 ◽  
pp. 1-18
Author(s):  
Luciano Piubelli ◽  
Giulia Murtas ◽  
Valentina Rabattoni ◽  
Loredano Pollegioni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Amino Acid ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Main Role ◽  
Receptor Modulation ◽  
Improve Life Expectancy

Alzheimer’s disease (AD), the main cause of dementia worldwide, is characterized by a complex and multifactorial etiology. In large part, excitatory neurotransmission in the central nervous system is mediated by glutamate and its receptors are involved in synaptic plasticity. The N-methyl-D-aspartate (NMDA) receptors, which require the agonist glutamate and a coagonist such as glycine or the D-enantiomer of serine for activation, play a main role here. A second D-amino acid, D-aspartate, acts as agonist of NMDA receptors. D-amino acids, present in low amounts in nature and long considered to be of bacterial origin, have distinctive functions in mammals. In recent years, alterations in physiological levels of various D-amino acids have been linked to various pathological states, ranging from chronic kidney disease to neurological disorders. Actually, the level of NMDA receptor signaling must be balanced to promote neuronal survival and prevent neurodegeneration: this signaling in AD is affected mainly by glutamate availability and modulation of the receptor’s functions. Here, we report the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions. Interestingly, AD progression has been also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism. Furthermore, the D-serine and D-/total serine ratio in serum have been recently proposed as biomarkers of AD progression. A greater understanding of the role of D-amino acids in excitotoxicity related to the pathogenesis of AD will facilitate novel therapeutic treatments to cure the disease and improve life expectancy.

Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).

1995 ◽  
Vol 198 (7) ◽  
pp. 1621-1628 ◽  
Author(s):  
L T Buck ◽  
P E Bickler
Keyword(s):  
Cerebral Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Control Level ◽  
Chrysemys Picta ◽  
Receptor Modulation ◽  
A1 Receptor ◽  
Excitatory Neurotransmission ◽  
Similar Decrease

Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.

scholarly journals Cognitive Decline in Neuronal Aging and Alzheimer's Disease: Role of NMDA Receptors and Associated Proteins

2017 ◽  
Vol 11 ◽  
Author(s):  
Jesús Avila ◽  
María Llorens-Martín ◽  
Noemí Pallas-Bazarra ◽  
Marta Bolós ◽  
Juan R. Perea ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Nmda Receptors ◽  
Associated Proteins

scholarly journals N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Rafael Rivas-Santisteban ◽  
Alejandro Lillo ◽  
Jaume Lillo ◽  
Joan-Biel Rebassa ◽  
Joan S. Contestí ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptor ◽  
Transgenic Mice ◽  
Nmda Receptors ◽  
Mapk Pathway ◽  
Primary Cultures ◽  
Brain Slices ◽  
Receptor Complexes ◽  
Receptor Heteromers

Abstract Background The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. Methods Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). Results In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. Conclusions The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.

scholarly journals Role of Glutamate and NMDA Receptors in Alzheimer’s Disease

2017 ◽  
Vol 57 (4) ◽  
pp. 1041-1048 ◽  
Author(s):  
Rui Wang ◽  
P. Hemachandra Reddy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptors

scholarly journals d-Amino Acids and pLG72 in Alzheimer’s Disease and Schizophrenia

2021 ◽  
Vol 22 (20) ◽  
pp. 10917
Author(s):  
Yu-Jung Cheng ◽  
Chieh-Hsin Lin ◽  
Hsien-Yuan Lane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Gene Polymorphisms ◽  
Diagnostic Value ◽  
Acid Oxidase ◽  
Amino Acid Oxidase

Numerous studies over the last several years have shown that d-amino acids, especially d-serine, have been related to brain and neurological disorders. Acknowledged neurological functions of d-amino acids include neurotransmission and learning and memory functions through modulating N-methyl-d-aspartate type glutamate receptors (NMDARs). Aberrant d-amino acids level and polymorphisms of genes related to d-amino acids metabolism are associated with neurodegenerative brain conditions. This review summarizes the roles of d-amino acids and pLG72, also known as d-amino acid oxidase activator, on two neurodegenerative disorders, schizophrenia and Alzheimer’s disease (AD). The scope includes the changes in d-amino acids levels, gene polymorphisms of G72 genomics, and the role of pLG72 on NMDARs and mitochondria in schizophrenia and AD. The clinical diagnostic value of d-amino acids and pLG72 and the therapeutic importance are also reviewed.

scholarly journals Biomolecular Characteristics of Amyloid Precursor Protein Mutations As Causes of Alzheimer's Disease Analyzed Through Bioinformatics Media

2018 ◽  
Vol 1 (1) ◽  
pp. 61-73
Author(s):  
Irfannudin Irfannudin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Amino Acid ◽  
Amyloid Precursor Protein ◽  
Transmembrane Protein ◽  
Stability Index ◽  
Precursor Protein ◽  
Characteristic Change ◽  
Amyloid Angiopathy

Methods of biomolecular analysis on protein through bioinformatics media has been growing rapidly. This report is intended to describe the results of biomolecular amyloid precursor protein (APP) analysis and the characteristic change of APP mutations causing cognitive degeneration disorder through bioinformatics media and search to reliable biomolecular sites.  APP is a transmembrane protein that is widely present in neuronal tissue. APP plays an important role for the formation of neuronal cells. The APP gene is located on the 21st chromosome that has 290,586 base pairs (bp) of 20 exons and 19 introns. In the form of a protein, APP consists of 770 amino acids with major expressions located on the cell surface. Mutation of APP genes is believed to play a role in the incidence of Alzheimer's disease. One of the mutations studied in this paper is the mutation of Alanin to Glysin at the position of the 692 amino acid (APP mutant A692G). This mutation affects the impairment of cerebral amyloid angiopathy belonging to the Alzheimer Disease Familial-1 group.These mutations do not cause changes in predictions of secondary structures and only cause slight changes in molecular weight, amino acid composition, atomic composition, aliphatic index, hydroplasticity and stability index. APP A692G mutation does not alter topology, hydrophobicity, cutting prediction and protein location prediction. Mutation also removes only the side chains at the position of the mutated amino acids.

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