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ISIS Report - April 25, 2001

Where Genes Fail - Dietary Interventions for Alzheimer’s and Parkinson’s?

While the hunt for the genetic basis of Alzheimer’s and Parkinson’s continues, and ‘cure’ in the form of foetal cell transplant turned into nightmare, senior NIH scientist Richard Veech is developing a promising approach that will involve dietary intervention. Mae-Wan Ho reports.

A team, headed by Richard Veech, senior scientist in the United States National Institutes of Health (NIH), has made discoveries that may lead to a simple, effective treatment for Alzheimer’s and Parkinson’s diseases. A molecular shunt that feeds into the core metabolic cycle, can protect cultured neurons from the kinds of damages involved in those neurodegenerative diseases [1]. Veech was in exuberant, confident mood when I met him recently at a special workshop on the biophysics of aging, convened by gerontologist Dr. Walter Bortz in Berkeley.

Alzheimer’s disease affects 5 million and Parkinson’s disease about 500 000 in the United States. The incidence of Alzheimer’s is expected to increase as the population ages, as its prevalence rises from 2.5% of those at 65 years of age to 47% of those over 85 years of age. Patients lose recent memory; the neurotransmitter acetylcholine decreases in the brain, and neurons die in the part of the brain known as the hippocampus, where the protein fragment, Ab1-42, accumulate in characteristic plaques (patches). . Alzheimers disease is generally regarded as multi-factorial. Approximately 20% of cases appear related to abnormalities of Ab1-42 metabolism associated with genetic defects mapped to chromosome 1, 14, 19 or 21. That leaves at least 80% associated with other factors, which include brain trauma, ischemia (decreased blood flow) insulin resistance, or impairment of brain energy metabolism.

Parkinson’s disease symptoms include muscle rigidity and tremor of the hands, and is diagnosed by aggregates of the proteins asynuclein and ubiquitin in neurons, and death of neurons that use the neurotransmitter dopamine in the part of the brain known as substantia nigra. The disease can be associated with genetic abnormalities, environmental toxins or infections, and can be treated, at least temporarily, by the drug L-dopa. Experimentally, a syndrome indistinguishable from Parkinson’s disease can be induced by the heroin analogue, 1-methyl-4-phenylpyridinium (MPP+), which is taken up by the dopamine transporter protein into the neurons. In the neurons, MPP+ inhibits the activity of NADH dehydrogenase, the first enzyme of the ‘electron transport chain’ in the mitochondria, which oxidises the metabolic products of glucose in a core cycle of reactions – the tricarboxylic acid (TCA) cycle - that extract energy to power all living activities.

The brain uses a disproportionately large amount of energy for its weight, and it needs to extract it directly from glucose. The brain is unable to use fatty acids (breakdown products of fats) or amino acids (breakdown products of proteins), which can enter the TCA cycle through branch points in other tissues. A metabolite the brain can use is ketones, which can feed directly into the TCA cycle.

Richard Veech’s team found that ketones protect neurons from both MPP+, which induces Parkinsons disease, and the protein fragment Ab1-42, which accumulates in the brain of Alzheimers patients. Not only that, addition of ketones alone actually increased the number of surviving neurons from the hippocampus, suggesting that ketones may even act as growth factors for neurons in culture.

The team’s work goes back to the 1990s, when they started using ‘metabolic control analysis’ (see Box 1) to study glucose metabolism in working rat hearts perfused with glucose, to which ketones or insulin or both have been added [2]. Insulin is a hormone that reduces glucose concentration in the blood, and deficiency of insulin is associated with type I diabetes.

The metabolic web and metabolic control analysis

We eat to stay alive. Once inside the body, the complex foodstuff undergoes thousands of chemical reactions, known collectively as metabolism, that supply building blocks for growth and repair and extract energy to power all our living activities. Each of the chemical reactions in metabolism is catalysed by a specific enzyme. The metabolic pathways form an extremely complicated web, with many branch points and entangled cycles. The product of one enzyme is typically substrate for one or more other enzymes, and the activity of each enzyme is influenced by the concentration of its substrate and product, as well as cofactors, all of which are set by the activities of other enzymes. Thus, the properties of the whole cannot merely be a sum of its constituent parts. Equally, the properties of the parts within the whole are different from those they have in isolation. These considerations led Henrik Kacser and his colleagues in Edinburgh University to pioneer metabolic control analysis in the 1970s, which explicitly recognises the metabolic web as an interconnected whole, and it is impossible to change a single part without changing the whole. Metabolic control analysis examines the sensitivity of rates and fluxes to changes in enzymes and metabolite concentrations at both local and global levels [3]. Metabolic control analysis gave many important insights into the organisation of metabolism, confirming Henrik Kacser’s description of the metabolic web as “a molecular democracy of distributed control”. In other words, ‘control’ is shared over the entire network, and is contingent on the prevailing conditions.

Radioactive glucose was used to keep track of the rate at which glucose disappears and becomes transformed into different metabolites including glycogen (a storage product which is a large polymer of glucose). The results show that no single enzyme controls glucose metabolism. Instead, different enzymes are in control, depending on the prevailing conditions. For example, the heart works better in the presence of either ketones or insulin, but the combination of both ketones and insulin is no better than either alone. In the presence of glucose only, glycogen is broken down. With the addition of ketones, insulin or both, glycogen is synthesised. The concentrations of practically all the metabolites downstream of glucose are changed, many significantly, by the addition of ketones or insulin or both; as are the concentrations of the major energy intermediates, ATP and creatine phosphate.

At the same time, the effciency of the working heart increases by 25% in the presence of either insulin or ketones, and by 36% in the presence of both. The increase in efficiency is accompanied by dramatic changes in key metabolites in energy metabolism (those reactions leading directly to generating ATP in the mitochondria). The most interesting finding is that ketones appear to change the profile of energy metabolism in ways similar to insulin, which the researchers conclude, may have important clinical consequences. It has been shown previously that increase in blood ketones to levels observed after a 48h fast almost completely reversed the mitochondrial abnormalities associated with insulin deficiency. Moderate increases in circulating ketones, the authors suggest, “should be viewed as a beneficial compensation for insulin deficiency and perhaps also for geriatric patients or others with peroxidative damage to the processes of mitochondrial energy transduction” [4]. Could it be that ketones may also help type I diabetes?

The next obvious step is phase I clinical trial in Alzheimer’s and Parkinson’s patients. The problem is that ketones can’t be taken directly because they are too acidic. A trimer (a molecule that consists of three ketones joined end to end) is neutral, and would be suitable as a food supplement. The bad news for Veech is: no drug company will make the stuff for him, while the institution Veech works for, the NIH, does not even consider his research worth funding in the mad dash for genetic causes of diseases and gene-based drug and interventions.

The good news is that the Navy will be funding the project, so the clinical trial will go ahead after all. Watch this space.

For further details contact Dr. Richard Veech, e-mail: [email protected]

  1. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K and Veech RL. D-b-Hydroxybutyrate protects neurons in models of Alzheimers and Parkinsons disease. PNAS 2000: 97: 5440-4.
  2. Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL and Passonneau JV. Control of glucose utilization in working perfused rat heart. Journal of Biological Chemistry 1994: 269: 25502-14.
  3. See Kacser H. On parts and wholes in metabolism. In The Organization of Cell Metabolism (G.R. Welch and J.S. Clegg, eds), Plenum Publishing Corporation, 1987. For a more accessible account of metabolic control analysis, see Ho MW. Choreographer and dancer in Bioenergetics, S327 Living Processes, Bk 2 (M W. Ho ed.), Open University Press, Milton Keynes, 1995.
  4. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, Chance B, Clarke K and Veech RL. Insulin, ketone bodies, and mmitochondrial energy transduction. The Faseb Journal 1995: 9: 651-8.
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