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International Workshop on
Brain Uptake and Utilization of Fatty Acids: Application to Peroxisomal Biogenesis Diseases

Recommendations for Future Research

I. Agenda
II. Recommendations from March 3, 2000 Afternoon Session
III. Recommendations from March 4, 2000 Morning Session
IV. Recommendations from March 4, 2000 Afternoon Session
V. Participants
VI. Additional Link

I. Agenda

Thursday, March 2, 2000

Friday, March 3, 2000

Saturday: March 4, 2000

II. Recommendations from March 3, 2000 Afternoon Session

Plasma sources of PUFA

Although data from serum lipid composition suggest that a potential major source of brain PUFA is lipoprotein-associated complex lipids, few studies have as yet addressed specific details of PUFA transport and uptake by this mechanism. Numerous lipoprotein classes and glycerolipid pools may be involved. Thus, investigations directed at the identification and functional characterization of PUFA-selective lipoprotein classes and PUFA-enriched glycerolipid pools would be enlightening. It may be possible to utilize stable PUFA isotopes (¹³C or perdeuterated) to identify and follow these lipoproteins/glycerolipids in feeding studies.

Role of barrier cells and astrocytes in the uptake and processing of PUFA or lipoprotein-associated PUFA

Studies that parallel the focus on serum lipid composition (particularly lipoproteins) should also be directed at cells carrying out barrier functions between blood and neurons. Foremost among these barrier cells are cerebral endothelium of the blood-brain barrier, choroid plexus epithelium that produce the bulk of cerebrospinal fluid, and astrocytes that closely associate with both cerebral blood vessels and neurons. The distribution, molecular nature, and function of lipoprotein lipase, lipoprotein receptors, and intracellular mechanisms for lipoprotein processing or trafficking in these cells are some of the major areas that require attention.

Once PUFAs are free of their carrier proteins and/or glycerolipids, a different group of binding and transport proteins are likely to be important in directing the flow of PUFA across barrier cells or within the brain. In this regard molecular and cell biological approaches should be aimed at understanding how fatty acid binding proteins (FABP) and fatty acid transport proteins (FATP) are distributed and how they function. Attention should also be directed at the specificity of enzymes that esterify PUFA, since the selectivity observed in membrane lipids may be regulated significantly at the esterification level.

Finally, additional carrier proteins or glycerolipids are likely to be involved in the intercellular distribution of PUFA within the brain parenchyma. For example, astrocytes are known to be a source of apolipoprotein synthesis in the brain, but little is known about the function of brain apolipoproteins in the intercellular exchange of PUFA. The fact that the E4 allele of apolipoprotein E is a major risk factor for Alzheimer's disease provides a significant allure to this area of study.

Local synthesis of PUFA

Although there is strong evidence for local synthesis of long-chain PUFA by brain-derived cells, recent advances in the molecular and cell biology of desaturase enzymes and peroxisomal assembly have yet to be applied systematically to the brain. The application of this new knowledge, particularly using genetic engineering approaches, should provide the clearest

evidence yet on the role of local synthesis in the accretion of PUFA by brain. It might also provide a basis for developing molecular approaches to therapy in neurological disorders where long-chain PUFAs are deficient.

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III. Recommendations from March 4, 2000 Morning Session

Uptake rates of nutritionally supplied fatty acids by the brain

The method, model and "operational equations" presented at the workshop, for quantifying in vivo brain turnover rates and half-lives of fatty acids during uptake from plasma to the brain, can be applied to the elucidation of uptake rates of nutritionally -provided omega-6 PUFA (e.g. linoleic acid, LA; gamma-linolenic acid, GLA, arachidonic acid, AA), omega-3 PUFA (e.g. alpha-linolenic acid, ALA; eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) and of dietary saturated and monounsaturated fatty acids. In the case of saturated and monounsaturated fatty acids, studies could help clarify the possible differences between their uptake versus de novo synthesis in the developing and in the adult brains.

Effects of centrally acting drugs on the steady state of fatty acids

The above approach can also be applied to the assessment of changes in steady states in response to centrally acting drugs and pathological changes in bipolar and other disorders. When combined with neuroimaging intravenously injected radiolabeled PUFA can also be utilized to examine neuroplastic remodeling of brain fatty acids and lipid membranes.

Role of plasmalogens in glial and neuronal tissue

• It was noted that AA- and DHA-containing plasmalogens (the glycerophospholipids containing an enol-ether group at the sn-1 position) play important roles as potential protectors of neurons from oxidative stress and suppliers of free AA and DHA to the cell. They can function also as modulators of neuronal membrane physical state and permeability both in the developing and in the mature brain. Plasmalogens are formed in peroxisomes, therefore they could be involved in a wide range of pathological states such as peroxisomal biogenesis disorders (Zellweger's syndrome and neonatal leukodystrophy) as well as ischemia or neurodegerative diseases, such as Alzheimer's disease, and even spinal cord trauma. All of these issues warrant rapid further elucidation.

• It would also be important to understand the contribution of plasmalogens to the free fatty acid pool and therefore their contributions to prostaglandin-mediated processes in the developing and mature neuron in health and disease.

The role of DHA in the developing and adult brain

• Results reported in Session 2 and 3 settle neither the question whether saturated and monounsaturated fatty acids are taken up by the brain or whether they are synthesized de novo by the brain, nor the question whether developing brain is similar or identical with adult brain in this regard. Studies on the gene regulatory effects of EPA and DHA in the liver and other organs on lipogenic enzymes do not extend to the brain in a satisfactory fashion. A strong need exists in elucidating the molecular biology and genetics of brain lipogenesis and its regulation by long-chain, omega-3 fatty acids (EPA and DHA) in both the developing and the adult brain.

• The accelerated in utero uptake of DHA (by the rat embryo) appears characteristic both to animals and humans. Since the mother is the major supplier of DHA to the developing rat brain, a low circulating level of plasma DHA in the mother could lower the embryo's DHA brain levels. Direct intra-amniotic injection of DHA ethyl ester restores embryonic brain uptake of DHA to normal levels. Additional research into the mechanisms of DHA accretion and depletion in embryonic and developing rat brain and into the potential behavioral or cognitive consequences of below normal DHA levels in the embryonic and postnatal brain should shed light on why DHA and possibly AA supplementation of infant formulas would be important for normal brain development. Elucidating the consequences of DHA deficiency during the developmental period is especially important due to the reported potential role of DHA to protect the developing brain from oxidative stress.

• The extension of these in vivo studies to humans would render the development of appropriate non-invasive techniques for quantitation of neuronal changes due to DHA presence or absence including, but not limited to the development of new imaging and tracer approaches highly desirable.

• The question of the role of DHA in the management of environmental stress and oxidative stress in the adult brain is also worthy of exploration.

• A major breakthrough in understanding the role of DHA in signal transduction was recently reported in the outer rod segments (ROS) of the retina. It appears that the role of DHA in ROS membranes is attributable to its six double bonds that provide and ensure a "most favored" microenvironment in which rhodopsin can absorb a photon of light and undergo the rapid conformational changes that result in the activation of a G-protein. This activation initiates the chain of biochemical events in the visual transduction pathway that ultimately leads to hyperpolarization of the plasma membrane. This observation, based on solid methodological determinations indicates that the high concentrations of DHA in the rhodopsin the outer rod segments might be of paramount importance to efficient signal transduction. DHA might have similar functions in the transduction of the neuronal signals through the membrane and synapses. Validating this potential role of DHA in the different neurons of different areas of the brain and should contribute significantly to our understanding of the functioning of the central nervous system.

• It is also important to understand what implications does DHA deficiency, during brain development, have on neuronal signal transduction and transmission.

Intermediary metabolism of PUFA and brain disorders

Answers should be sought to questions involving post-uptake shuttling and metabolism of AA, EPA and DHA. Such questions are exemplified in the following: How does DHA, taken up by the brain through the BBB or synthesized from its precursors by astrocytic peroxisomes, reach its neuronal locations? Are there special DHA transporters in the brain? Are astrocytes mostly devoid of DHA and function primarily as elongation/ desaturation tools of EPA and its higher homolog docosapentaenoic acid (DPA)? What are the functions of EPA and DPA in astrocytes? Are EPA and DHA naturally segregated between astrocytes (EPA) and neurons (DHA)? What are the eicosanoids produced from EPA and what are their functions in the brain? What are docosanoids and what are their functions in the brain? Are these functions related to the pathophysiology of neuropsychobehavioral disorders such as: bipolar disorder, unipolar depression and schizophrenia? Do EPA, DPA and DHA exert the same therapeutic effect in these disorders? Etc.

DHA, EPA and apoptosis of glial and neuronal cells

-The finding that DHA can potentially inhibit neuronal apoptosis in two cell lines and that this inhibitory effect appears related to an increase in PS concentration raises several questions on yet another potential physiological role of DHA namely that of long-term survival of the neuronal cell. Does depletion of DHA result in neuronal death? If that effect of DHA is proven, is this effect reversible? Is there a connection between DHA depletion and the pathophysiology of inherited neurodegenerative diseases or Alzheimer's disease? Is the anti-apoptotic effect of DHA responsible for its apparent segregation to the neuron? What would be the consequences of long-term DHA storage in astrocytes, which appear to eliminate free DHA as it is formed from its precursors. How would the anti-apoptotic effect persist in animal models? All of these questions deserve to be answered.

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IV. Recommendations from March 4, 2000 Afternoon Session

Therapeutic interventions in peroxisomal biogenesis disorders

Last updated July 09, 2008