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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:
rveech@dicbr.niaaa.nih.gov
- 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.
- 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.
- 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.
- 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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