Serine is a non-essential amino acid that is critical for the synthesis of phosphatidylserine (PS) — the phospholipid that is essential for the function of cell membranes in the brain, for the activity of the protein kinase C (PKC) signalling pathway, and for the maintenance of mitochondrial structure and function. Serine is synthesised from the glycolytic intermediate 3-phosphoglycerate and is the precursor of three of the most important lipid signalling molecules in the brain — phosphatidylserine, phosphatidylethanolamine, and sphingomyelin — as well as of the amino acid glycine and of the methyl donor dimethylglycine. This serine-centred network of lipid and methyl group metabolism is one of the most important metabolic pathways in the brain, and its dysfunction is implicated in the cognitive impairment, the neurodegenerative disease, and the metabolic dysfunction that characterise the conditions in which serine metabolism is impaired.
Phosphatidylserine and Cognitive Function
Phosphatidylserine is a phospholipid that is highly enriched in the inner (cytoplasmic) leaflet of the neuronal cell membrane, where it serves as the anchor for many of the signalling proteins that are critical for synaptic function, including the protein kinase C (PKC) isoforms that are involved in the regulation of learning and memory. PKC is activated by diacylglycerol (DAG) and by phosphatidylserine, and the PS-dependent activation of PKC at the synaptic membrane is one of the primary mechanisms by which synaptic activity is translated into the changes in gene expression that underlie long-term potentiation (LTP) and long-term depression (LTD) — the cellular correlates of learning and memory. The importance of phosphatidylserine for cognitive function is supported by the observation that phosphatidylserine supplementation (at 100-300mg daily) has been shown in multiple RCTs to improve cognitive function in older adults with mild cognitive impairment and with Alzheimer disease, with improvements in memory, attention, and processing speed that are clinically meaningful and that are apparent within 6-12 weeks of starting supplementation.
The mechanism of the cognitive benefits of phosphatidylserine supplementation is thought to involve the restoration of the phosphatidylserine content of neuronal membranes, which declines with age and which is accelerated in Alzheimer disease. When the phosphatidylserine content of neuronal membranes is reduced, the activity of the PS-dependent signalling proteins (including PKC and the other proteins that require PS for their membrane association) is impaired, and the synaptic plasticity that underlies learning and memory is compromised. Phosphatidylserine supplementation restores the PS content of neuronal membranes and thereby improves the activity of the signalling proteins that are critical for cognitive function. The evidence for phosphatidylserine in cognitive impairment is moderately strong — a meta-analysis of 10 RCTs found that phosphatidylserine supplementation significantly improved cognitive function in older adults with age-related cognitive decline, with the greatest benefits seen in people with the most severe impairment.
Serine and the Glycine Methylation System
Serine is also the precursor of glycine via the enzyme serine hydroxymethyltransferase (SHMT), which converts serine to glycine and generates the one-carbon unit that is transferred to the methylation cycle. This serine-glycine-methylation connection is clinically important because the one-carbon units that are generated by the serine-to-glycine conversion are the primary source of the methyl groups that are used in the methylation of DNA, RNA, proteins, and neurotransmitters. When serine availability is inadequate, the flow of one-carbon units from serine to the methylation cycle is reduced, the methylation cycle is impaired, and the downstream methylation reactions that are essential for gene regulation and for neurotransmitter synthesis are compromised. This serine-methylation connection is one of the mechanisms by which serine deficiency may contribute to the cognitive impairment and the mood dysregulation that are associated with inadequate one-carbon metabolism.
Practical Application
For general serine and phosphatidylserine supplementation, the evidence-based dose is 1,000-2,000mg of phosphatidylserine daily (from bovine cortex or from soy-free plant sources such as sunflower lecithin, which is the preferred source for vegetarians and vegans) and 500-1,000mg of L-serine daily as an adjunct to phosphatidylserine for its additional effects on membrane composition and on the glycine methylation system. Phosphatidylserine is generally well-tolerated with no significant adverse effects at therapeutic doses, though it can produce mild GI upset at high doses. For comprehensive cognitive support, serine and phosphatidylserine pair well with the omega-3 fatty acids (which are the precursors of the docosahexaenoic acid (DHA) that is highly enriched in neuronal membranes and that is essential for synaptic function), with acetyl-L-carnitine (which supports mitochondrial function in neurons and which has been shown to improve cognitive function in older adults), with huperzine A (an acetylcholinesterase inhibitor from the Chinese club moss Huperzia serrata, which improves synaptic cholinergic function by preventing the breakdown of acetylcholine), and with the Mediterranean dietary pattern (which is associated with slower cognitive decline and with reduced risk of Alzheimer disease, likely through its effects on membrane lipid composition and on the inflammatory status of the brain).
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