PS Phosphatidylserine An essential building block for a healthy brain Scientific summary 1 Cell exterior Receptor Serine Cell interior PS Phosphate PS PS PS Glycerol PS PS 1 Introduction PS PS PS PIP3 PIP2 Cell Ras Diet PKC P interior P AKT PI3K PS PS P Protein PS MEK Raf P P PS Serine Fatty acid Fatty acid PS Lipids are a major component of the cell membrane and serve multiple functions. They help in maintaining membrane Table 2 Normal age-related changes in brain most lipids going down after 50 years of age.(8) Total PLs structure and fluidity, function as an energy reserve, and participate in key cell signaling pathways.(3,4) Each of these membrane lipidsSynaptic (8-10, 12,13) Neuronal survivalundergo a steady yet slow decline between 20 and 80 years, functions is determined by the distribution of different lipids (structure,Choline/ amount, and proportion) across the body; even a transmission and differentiationafter which the reduction becomes more pronounced.(8) PE small alteration can generate differences in how cells perform.(4) ethanolaminePhosphatidylserine (PS) is one among a classCell of lipids exterior called and PC decrease very slowly after the age of 40 years, with a phospholipids (PLs), which play a critical role in membrane structure and signaling, in turn modulating how a cell functions.(3) loss of ≤10% thereafter.(8) PS levels, on the other hand, Decade Total lipid Total PLs PS remain constant between 10 to 33 years of age and decline PC/PE rapidly thereafter.(2, 7-13) The PS-to-cholesterol ratio of the 1 neuronal cell membrane also goes down.(8-13) In addition, 1.1 Phospholipids: the building blocks of cell aging reduces the content of long chain polyunsaturated membrane structure Figure 1 PS, an essential building block of 2 fatty acids (LC-PUFA; 20:4n-6, 22:6n-3) of PS, while The fundamental structure of the human cell membrane brain cells increasing its monounsaturated fatty acid (MUFA; 18:1n-9, is a phospholipid bilayer, peppered with proteins and 3 (~33 years) 20:1n-9) content.(14) carbohydrates bound to either proteins or lipids.(1,2) (>33 years) Approximately 50% of the mass of most cell membranes The altered brain lipid composition seen in aging is Cell interior is phospholipids (PLs), glycolipids, and cholesterol.(1-3) Serine PS associated with a number of structural and biochemical PS 4 A typical human cell membrane contains four major PLs properties of the membrane. Structural changes, mainly an Phosphate PS PS (phosphatidylserine, phosphatidylcholine, PS PS increase in viscosity, is brought about by a reduction in the Glycerol PS 5 phosphatidylethanolamine, and sphingomyelin), and one PS PS PS-to-cholesterol ratio and can impact the activity of quantitatively minor PL (phosphatidylinositol).(1-3) 6 membrane-bound enzymes and receptors that require These PLs and their arrangement are the core structure PS PS optimal fluidity.(15) Protein of the membrane and what keeps animal cells intact. PS 7 All cell membranes share the same phospholipid bilayer Fatty acid 1.3 Modern day dietary patterns reduce PS Fatty acid 8 structure but differences in the fatty acid composition of intake individual PLs can influence membrane fluidity, permeability, 9 The human body can synthesize PS de novo from substrate and signaling functions.(3) Furthermore, PL distribution in Cell exterior PLs (PC and PE), but PS is also obtained through foods such the bilayer is asymmetric, with PC and SM in the outer as fish, milk, rice and beans.(16,17) The composition of (extracellular-facing) leaflet, and PE and PS in the inner today’s diets can be important in this regard. (cytoplasm-facing) leaflet.(1) The maintenance of this 1.2 PS is essential for membrane function, but distribution is not only essential for cell function but also for declines with age The traditional Mediterranean diet, for instance, emphasizes their survival. In healthy cells, PS is preferentially found on the inner leaflet a variety of foods with a balanced nutrient profile that of the lipid bilayer, where it helps influence membrane includes a high intake of fruits, vegetables, cereals, and structure and fluidity. The presence of double bonds in the legumes, a moderate consumption of fish, and a high intake fatty acid tails of DHA-enriched PS prevents it from packing of olive oil but a low consumption of saturated fats. closely together, thereby increasing the membrane’s fluidity This balanced composition serves as a source of PS, other and flexibility.(2, 7) Additionally, PS plays essential roles in key lipids, and nutrients that support a variety of cellular Table 1 Lipid composition of cell membranes (% of total lipids) (5,6,11,22,54,55) the cell by modulating cell signaling pathways.(3) PS can also functions. On the other hand, modern diets tends to be translocate to the outer leaflet of the bilayer in an irreversible higher in saturated fats and carbohydrates, but lower in fiber, mechanism used by apoptotic (dying) cells, thereby flagging essential fatty acids, and important nutrients like PS.(18) Lipid* Typical membrane (%) Brain tissue (%) them for recognition and engulfment by the phagocytes in Modern-day diets have, indeed, reduced PS intake by charge of their disposal.(3) Hence, despite being only 10% or approximately 48% across all age groups.(19) Eating more Cholesterol 34 37 less of total membrane lipids (Table 1), PS levels and its foods that are naturally rich in PS is one way of increasing asymmetrical distribution within the inner leaflet is critical intake. However, supplementation may be needed to ensure Phosphatidylcholine (PC) 23 19 to the cell’s healthy function and survival. daily intake of PS at levels sufficient to restore balance.(19) Sphingomyelin (SM) 17 6.0-10 Normal aging is accompanied by quantitative and qualitative changes to the overall lipid composition of the brain. (8) Phosphatidylethanolamine (PE) 11 17 Studies have been presenting evidence of these age-related changes since the 1950s. The human brain’s total lipid Phosphatidylserine (PS) 10 10 content increases during the first two decades of life, after which it begins to decrease,(9, 10) with concentrations of *Only includes lipids constituting ≥5% of the total lipids 2 3 2 PS is essential for neuronal function 2.1 PS in the human brain 2.2 PS role in neuronal survival 2.3 PS role in synaptic transmission The human brain not only has the second highest lipid content PS is localized exclusively in the cytoplasmic leaflet of Communication between neurons starts when vesicles filled with neurotransmitter fuse with the membrane of a neuron, the (after adipose tissue) among tissues in the body, it also has neuronal membranes. Being an acidic phospholipid, its presynaptic neuron. This event releases neurotransmitter into the synapse, allowing it to reach receptors in the receiving, or one of the most unique lipid compositions.(20,21) Lipids intracellular portion is negatively charged at cellular pH. postsynaptic, neuron. Calcium (Ca2+) entering the presynaptic neuron is the trigger for neurotransmitter release. PS is involved in make up to 40-55% of the brain’s dry weight, This charge makes PS interact with proteins, promoting their this Ca2+ influx and enhances the binding affinity for Ca2+ of Synaptotagmin I, a key component of the machinery involved in compared to 6-20% for other organs. PLs constitute 50% of translocation to the membrane’s proximity. Localization at neurotransmitter release.(16, 56, 57, 58) At the postsynaptic end, PS has been shown to influence the levels of receptors for the those lipids.(21,22)PS makes up 10% of total brain lipids and the membrane enables cell signaling proteins to interact with neurotransmitter glutamate, through the action of the enzyme Phosphokinase C (PKC). Regulation of glutamate receptor levels is the major acidic PL in the brain.(16) It is enriched in the intracellular portion of membrane receptors, it enables supports synaptic plasticity, the property of synapses that allows them to mediate learning and memory.(25, 59-64) unsaturated fatty acids, including oleic acid (OLA; 18:1n-9), their activation by membrane-bound enzymes, or induces docosahexaenoic acid (DHA; 22:6n-3), arachidonic acid conformational changes that trigger further activation of (ARA; 20:4n-6), and docosatetraenoic acid (DTA; 22:4n-6). downstream proteins. The direct participation of PS in these (11, 23) signaling cascades, especially those involving proteins Raf-1 and Akt, makes it essential for the cellular mechanisms Table 4 Major PS-dependent signaling pathways that influence neuronal function involved in neuronal survival.(16, 24) (Figure 2 and Table 4) Pathway Role of PS Impact on neuronal function Raf-1 (16, 66, 67) PS is required for activation of Raf-1 Inhibits apoptosis leading to which in turn activates downstream MEK/ neuroprotection and cell survival Figure 2 PS-dependent neuronal signaling pathways (16) ERK signaling and inhibits caspase-3 activity Cell Akt (16, 26, 67) PS secures the translocation and • Supports neuronal differentiation and exterior Receptor Serine Cell interior membrane binding of Akt leading to its survival PS activation • Modulates synaptic transmission by Phosphate PS regulating postsynaptic receptor levels PS PS PS Glycerol PS Synaptotagmin I (68) PS and PI binding to Synaptotagmin I Enables neurotransmitter release PS 2+ PS PIP PIP enable its ability to sense Ca PS 3 2 Ras Diet Cell P PKC AKT 2+ PS interior P PI3K Protein kinase C (PKC) (16, 56, PS interacts with PKC, in a Ca - • Modulates neurotransmitter release PS P 61, 69) dependent manner, to enable its • Modulates synaptic transmission by Protein Raf P PS MEK membrane translocation regulating postsynaptic AMPA and P PS NMDA glutamate receptor levels Serine Fatty acid Fatty acid PS Synaptic Neuronal survival Choline/ transmission and differentiation ethanolamine Cell exterior PC/PE Cell interior Serine PS PS 4 5 Phosphate PS PS PS PS Glycerol PS PS PS PS PS Protein PS Fatty acid Fatty acid Cell exterior 3 PS and cognitive function Factors like demographics, genetics, dietary patterns, and age can alter lipid homeostasis.