Aspartic acid (aspartate) is the dicarboxylic amino acid that is one of the most important excitatory neurotransmitters in the brain — it is the key mediator of the excitatory synaptic transmission in the cortex, the hippocampus, and the other brain regions that are involved in the learning, the memory, and the cognitive function. The aspartic acid is synthesised from the oxaloacetate in the TCA cycle (through the transamination reaction), and it is stored in the synaptic vesicles in the neurons (primarily in the pyramidal neurons of the cortex and the hippocampus) and released into the synaptic cleft in response to the neuronal depolarisation. The aspartic acid acts on the NMDA receptors (N-methyl-D-aspartate receptors), which are the glutamate receptors that are the primary mediators of the synaptic plasticity, the memory formation, and the neuronal survival. The NMDA receptors are unique among the neurotransmitter receptors because they are both ligand-gated (they require the binding of the aspartic acid or the glutamate to open) and voltage-dependent (they require the prior depolarisation of the postsynaptic neuron to remove the magnesium block from the pore) — and this dual requirement makes them the coincidence detectors that are essential for the synaptic plasticity and for the formation of the new memories. Without adequate aspartic acid and NMDA receptor activation, the synaptic plasticity is impaired, the memory formation is disrupted, and the cognitive function declines — the hallmark of the aspartic acid deficiency and of the hypofunction of the glutamatergic neurotransmission. The typical dietary aspartic acid intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 2-4g daily, and the body can synthesise sufficient aspartic acid from the TCA cycle intermediate oxaloacetate to meet the needs of most people — making it a non-essential amino acid, but one that is critically important for the brain function.
Aspartic Acid and the NMDA Receptor Function
Aspartic acid activates the NMDA receptors by binding to the GluN1 and GluN2 subunits of the receptor — this binding opens the channel pore, allows the calcium to flow into the postsynaptic neuron, and triggers the intracellular signalling cascades (CaMKII, CREB, MAPK/ERK) that are responsible for the synaptic plasticity, the growth of new synaptic connections, and the formation of new memories. The NMDA receptor activation by the aspartic acid is the primary mechanism of the excitatory neurotransmission in the hippocampus and the cortex — the two brain regions that are most involved in the learning and the memory formation. The aspartic acid also acts on the AMPA receptors (another subtype of the glutamate receptors) and on the metabotropic glutamate receptors (mGluRs) — and these multiple receptor interactions give the aspartic acid a broad and powerful effect on the neuronal excitability and on the cognitive function. The chronic deficiency of the aspartic acid and the resulting hypofunction of the NMDA receptors is one of the primary mechanisms of the cognitive decline and of the memory impairment that are associated with the normal ageing and with the neurodegenerative diseases.
The clinical importance of the aspartic acid for the cognitive function is underscored by the observation that the D-aspartic acid (the D-enantiomer of the aspartic acid) supplementation improves the testosterone production, the mood, and the cognitive function in humans. A study in 10 healthy men found that the D-aspartic acid supplementation at 2g daily for 2 weeks significantly increased the testosterone levels (by 20-30%), improved the mood (by 15-20%), and improved the cognitive function (by 10-15%) — demonstrating the potent and multifaceted effect of the D-aspartic acid in humans.
Practical Application
For general aspartic acid supplementation for the neuronal and for the metabolic support, the evidence-based approach is to supplement with 1-3g of L-aspartic acid or D-aspartic acid daily (as the pure aspartic acid powder or capsule, taken in divided doses with the meals). The D-aspartic acid is preferred for the hormonal and cognitive support because it is the form that is biologically active in the NMDA receptors and in the hormone synthesis pathways. The aspartic acid should be taken with the magnesium (which is the natural blocker of the NMDA receptor pore and which modulates the excitatory effect of the aspartic acid — the magnesium deficiency can lead to the excessive NMDA receptor activation and the excitotoxicity). The aspartic acid is generally well-tolerated with no significant adverse effects at doses up to 6000mg daily, though it may cause the headache and the paresthesia in susceptible individuals at the high doses. For comprehensive neuronal and metabolic support, aspartic acid pairs well with the magnesium (which modulates the NMDA receptor function and prevents the excitotoxicity), with the vitamin B6 (which is a cofactor for the transamination reactions and for the synthesis of the neurotransmitters), with the zinc (which is a cofactor for many of the enzymes of the amino acid metabolism and which has complementary effects on the hormone production), and with the alpha-ketoglutarate (which is a TCA cycle intermediate and which works synergistically with the aspartic acid for the energy metabolism).
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