Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease. Docosahexaenoic acid (DHA), an essential omega 3 fatty acid, is uniquely concentrated in the brain, nervous tissues and retina, and is essential for the normal neurological development and function. The deficiency of DHA is associated with several neurological disorders, including Alzheimer's, Parkinson's, schizophrenia, and depression [1][2][3][4][5] . Unlike liver, the brain cannot efficiently convert dietary alpha linolenic acid (18:3, n-3) to DHA 6,7 , and is almost completely dependent upon the uptake of preformed DHA from the plasma. However, dietary supplementation with the currently available preparations of DHA such as fish or krill oil 8 , algal DHA 9 , DHA-enriched egg phospholipids 10 ethyl esters 11 and sardines 12 does not appreciably increase brain DHA levels in adult mammals, although peripheral tissues are enriched with DHA under the same conditions. One possible explanation for this is that DHA from the above supplements is hydrolyzed to free DHA by the pancreatic enzymes and absorbed as triacylglycerol (TAG) in chylomicrons (Fig. 1), whereas the brain uniquely takes up DHA in the form of lysophosphatidylcholine (LPC) [13][14][15] . The recent demonstration of a transporter at the blood brain barrier (Mfsd2a), which specifically transports LPC-DHA, but not free DHA
16, further supports this mechanism. It is therefore necessary to increase the levels of LPC-DHA in plasma for an efficient enrichment of brain DHA. We propose that if dietary DHA is provided in the sn-1 position of phosphatidylcholine (PC) or in the form of LPC in the diet, it should escape the hydrolysis by pancreatic PLA 2 , and will be absorbed as PC-DHA (Fig. 1). The PC-DHA is more likely to be taken up by the brain after conversion to LPC-DHA in plasma or liver by the phospholipases, compare...