Winter 2000 Issue — Phosphatidylserine (PS) and Cognition

Dr Kiran Virmani

SKW Bioactives

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Phosphatidylserine (PS) is a naturally occurring phospholipid whicb attracts attention of the general public due to its documented beneficial effects on cognition. The typical structure of phospholipids includes a glycerol backbone which forms the centre of the molecule. The first and second carbon atom of the glycerol backbone are esterified to fatty acids which form the lipophilic part of the molecule. Due to their molecular structure containing a lipophilic part and a hydrophilic part phospholipids are amphiphilic molecules which have emulsifying and surfactant properties and form bilayer structures in water.

In 1941, phosphatidylserine was identified as a constituent of the cephalin fraction of the brain.(1) Since then many papers on this substance were published. A program of clinical trials was supported by an Italian pharmaceutical company in the 70s(2) and beginning of the 80s PS extracted from bovine brain was marketed. Due to tbe occurrence of BSE (bovine spongiforme encephalopathy) the product was taken from the market mid of the 90s. PS also occurs in a plant derived source, namely in soybeans, but soybeans contain only very small amounts of PS. Thus, a method was developed to produce a soybean derived PS by exchanging the head group of phosphatidylcholine which is the main phospholipid in terms of content in soybeans enzymatically using a specific phospholipase. This product is on the market since about mid of the 90s.

In the body, phosphatidylserine is an important building block of all cell membranes, but it is found in highest concentration in the brain where it comprises 10-20% of the total phospholipid pool.(3,4) PS is located mainly in the inner leaflet of the cell membrane which is typical for phoospholipids containing an acidic head group. The acidic head group is also responsible for the tendency of PS to associate with membrane proteins.

Phosphatidylserine bas different structural and also regulatory functions in the brain cell membranes. One of the structural functions is the stabilization of the cell membrane by associating with membrane proteins and thus anchoring them in the membrane.(5) Another function is the involvement in repair mechanisms of the cells: PS flips to the outer cell membrane if a cell has been damaged or old signalling that the cell has to be repaired or recycled. PS is also involved in the regulation of many metabolic processes(4)such as activation of cell membrane bound enzymes: PS activates protein kinase C, an enzyme which acts as a second messenger by activating other membrane-bound enzymes. The sodium-potassium stimulated enzyme ATPase is also activated by PS. This enzyme regulates the sodium-potassium gradient and the calcium-magnesium gradient between the interior and exterior of the cells. Another enzyme activated by PS is tyrosine hydroxylase which is involved in tbe synthesis of neurotransmitters involved in signal transduction in the brain such as dopamine or norepinephraine.(3-5) PS is also involved in the activation of some other enzymes which are not mentioned here. Moreover, PS facilitates the calcium uptake into the cell. This is important for the activity of calcium dependent enzymes such as protein kinase C.(6)

A variety of clinical studies has been performed with PS showing the positive effects on memory, concentration, mood and behaviour in different study populations. A number of studies was conducted in persons with age related cognitive decline.

Age related cognitive decline (ARCD) is the diagnostic term for a physiological loss of memory and cognition(17) which can occur during middle age (around fifty years of age) or later and can result in a memory loss up to 50% of the initial capacity. People with ARCD have an impaired capacity of recalling names, faces and numbers.(7) The physiological decline in cognition is caused by biochemical and structural changes in the brain:(7-11) changes in membrane lipid composition and lipid content occur, the synthesis, release and metabolism of neurotransmitters decreases and enzyme activities decrease in this physiological process It has been shown that PS is able to cross the blood brain barrier(3) and counteract the metabolic and structural changes in the brain caused by ageing processes:(13, 14) PS enhances the activities of membrane bound enzymes involved in neurotransmitter release and signal transduction such as protein kinase C, Na/K­ATPase and tyrosine hydroxylase which decline with ageing.(3-5, 12, 13) Administration of PS induces a large increase in acetylcholine release in the brain.(3, 5, 14)

The effects of PS on brain glucose metabolism have been investigated using positrone emission tomography (PET) showing that PS induces a significant increase in cerebral glucose metabolism of defined cortical and subcortical structures of the brain.(15) Moreover PS counteracts the structural changes of ageing by preventing age-induced loss of dendritic spines and by reducing cell death and atrophy of cholinergic neurons.(16)

Thus, PS is able to reduce the severity of physiological neurochemical and morphological changes occurring with ageing.(4)

The clinical effects of PS were investigated in several double-blind, placebo-controlled clinical studies(7,8,17-19) using validated, objective psychological test methods.(20, 23) By means of such validated psychological tests the cognitive abilities of the participants were assessed. One of the studies investigating the effect of PS in ARCD even demonstrated an improvement of age related memory decline of up to 12 years depending on the memory task assessed. This means that the memory performance was improved to the level of memory performance of a person which is actually 12 years younger than the test person was.(24) Many of these studies were performed with animal derived PS in a daily dosage of 300 mg which was found to be effective. It was suggested to use 300 mg PS per day as a starting dose and to use 100 mg PS/day as a maintenance dosage.(24) It has been shown that PS derived from soy is as effective in improving the cognitive abilities in ARCD.(24) A comparison of the effects of PS derived from soybean and PS derived from bovine brain has been done in rats and mice(25) and recently in rats.(26) An indirect comparison of the effects of animal derived PS and soybean derived PS in humans has been performed by pooling tbe data from two human studies.(24) It has been shown that the beneficial effects of PS on cognition are comparable.

The clinical effects of PS are not limited to an improvement of memory tasks such as remembering names, face and numbers (7, 17, 18, 24, 28) but also include improvements in learning, concentration, mood and behaviour: it has been observed that the interest in the environment and the attention span were increased while loss of motivation, socialisation and initiative were reduced. (8, 18, 29)

In conclusion, PS is a very interesting substance effecting in counteracting ARCD. The effects of PS are not only limited to an improvement of memory tasks, but also include improvements of mood and behaviour and tasks of the daily life such as concentration and attention. In the meantime investigations on the effects of PS in other study populations than elderly people with ARCD are ongoing and it will be interesting to see if there are beneficial effects also in these other study populations.

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