Reversing Alzheimer’s and Parkinson’s

While the brain makes up only about 2 percent of a person’s body weight (depending on the person), at rest, it consumes about 20 percent of the total energy the body needs.

Tissues with a high demand for energy are uniquely dependent on mitochondria – the structures within cells that are responsible for most of the body’s energy production – and, therefore, also have the lowest threshold for showing signs of mitochondrial dysfunction. Since large amounts of energy are required by neurons (nerve cells) to carry out their specialized functions, the central nervous system is often one of the first systems to display obvious symptoms of energy deficiencies.

The brain is a giant tangle of countless neurons, so it would stand to reason that this organ might suffer significantly from mitochondrial dysfunction, and possibly respond well to mitochondrial nutrients.

Mitochondrial involvement in neurodegeneration

As early as 1999, scientific reviews began to summarize the growing body of evidence on the role of the mitochondria in neurodegeneration. As one review by researchers at the University of Virginia Health Sciences Center stated, “It is becoming clear that subtle functional alterations in these essential cellular dynamos can lead to insidious pathological changes in neurons.”1

The authors outlined a theory of neurodegeneration based upon a vicious cycle of DNA mutation, energy decline and free-radical damage – the same story now seen in a number of other disorders and confirmed by further studies over the last 20 years.

Studies like this now support the role of abnormal mitochondrial dynamics in neuronal cell death and the onset of Alzheimer’s, Parkinson’s, Huntington’s disease
and other neurodegenerative disorders. Although many health conditions, age-related changes, and neurodegeneration have similar basic causes, the physiology of the brain is unique in certain ways, and its pathologies present some interesting mechanisms and features.

The vulnerable brain

The brain is particularly vulnerable to free-radical damage (due to its high oxygen supply and high fat content), so it might seem logical to assume the brain’s antioxidant defense system is especially powerful.

Unfortunately, it is not, and this delicate organ is relatively under-defended against free-radical damage. As a result, the cells of the brain gradually accumulate oxidative damage over time. This is true for everyone but is of particular concern for
those with a genetic or environmental predisposition to neurological degeneration.

Most of the brain’s fat content is contained in the cell membranes, the long ‘arms’ and ‘branches’ (called axons and dendrites) that extend out from the cell body, and their mitochondria. As we age, more of these lipids become
oxidized due to exposure to the brain’s high levels of oxygen and free radicals, and the brain’s vulnerability to degenerative diseases increases.

Maintaining mitochondrial health is an important strategy in preventing this slow decline in our mental faculties as we age.

In the late 1980s, scientists at the National Institutes of Health (NIH) proposed that excitotoxicity (toxicity from overstimulation of nerve cells) develops when the energy level of neurons declines.2

The neurotransmitter glutamate normally transmits excitatory impulses from one neuron to another (see box, right). In neurodegeneration, however, the brain becomes chronically oversensitive to glutamate, which then becomes a slow-acting “excitatory toxin” to brain cells.

For mitochondria, this means that they are constantly under the direction to produce more energy – more than the neurons actually need. With this higher rate of activity comes a higher rate of free-radical production, and over time this leads to the accelerated demise of these mitochondria. Eventually this chain of events results in dysfunction within the neurons.

Building upon their discovery that the presence of mitochondria near a synapse affected the strength of neuron signaling (see box, page 30), NIH researchers manipulated mitochondrial movement by changing levels of syntaphilin, a protein that helps anchor mitochondria inside the axons.

Removal of syntaphilin resulted in mitochondria that moved more quickly, and the electrical recordings from these neurons showed that the signals they sent fluctuated greatly.

By contrast, elevating syntaphilin levels slowed mitochondrial movement and resulted in boutons that sent signals with a consistent strength.

The researchers also found that blocking mitochondrial production of ATP, the molecule responsible for storing cellular energy, reduced the strength of the signals sent, even if the mitochondria were near the boutons. Problems with mitochondrial energy production and movement throughout neurons have been implicated in Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS, also called motor neuron disease) and other major neurodegenerative diseases; this 2013 research adds a key piece to the puzzle and gives us more reason to target mitochondria and cellular energy in these illnesses.3

How the brain degenerates

At the cellular level, brains affected by Alzheimer’s disease show an extensive loss of neurons and high levels of insoluble fibrous deposits known as senile plaques and neurofibrillary tangles. At the core of the plaques is a toxic protein called amyloid beta – the hallmark of Alzheimer’s – that attacks cells on several fronts. Amyloid beta generates free radicals, damages mtDNA, impairs cellular bioenergetics and alters the proper folding of other proteins that go on to form the neurofibrillary tangles.

However, there is evidence to suggest that the formation of amyloid beta is the brain’s way of defending against oxidative stress. In other words, amyloid beta is a consequence of Alzheimer’s, not a cause.

The most current research shows we need a greater focus on mitochondria in the prevention and treatment of the disease. According to the results of some studies, the degree of disability in Alzheimer’s disease correlates with the level of bioenergetic impairment in the brain. In fact, a recent review suggests that cellular energy produc
tion might be a better indicator of Alzheimer’s disease severity than senile plaques.4

In one study from what is now called the Burke Neurological Institute, the degree of patients’ clinical disability did not correlate with the density of senile plaques but did correlate with a mitochondrial abnormality involved in cellular energetics.5 One important source of oxidative stress in the brain is a potent free radical called peroxynitrite (formed from nitric oxide), which oxidizes the lipids (fats), in the membranes of nerve cells.

This generates the highly toxic byproduct hydroxynonenal (HNE), which is found in excess levels in multiple brain regions of Alzheimer’s patients. HNE kills brain cells not only directly but also indirectly by making them more susceptible to excitotoxicity.

Current research has not identified a single underlying cause of Alzheimer’s disease, but an interesting multiple-factor theory was proposed by Wan-Tao Ying of the University of New Mexico in 1997.6 According to this theory, Alzheimer’s disease develops from the interplay of four causes: imbalances in APP (amyloid precursor protein), calcium, free-radical damage, and energy deficit. Ying’s research cites studies showing that each factor reinforces, and is reinforced by, each of the other factors.

Parkinson’s: beyond L-dopa

New research shows that mitochondrial dysfunction and impaired cellular energy production play a major role in the progression of Parkinson’s disease. Studies on animal models of Parkinson’s suggest that coenzyme Q10 (CoQ10), an antioxidant with a prominent role in mitochondrial function, can protect brain cells from neurotoxicity and excitotoxicity, even in cases where other powerful antioxidants cannot.

In Parkinson’s disease, cell death primarily occurs among the neurons in the substantia nigra – a part of the brain that coordinates movement. These neurons produce the neurotransmitter dopamine; the death of these cells depletes dopamine levels and ultimately leads to muscle rigidity, tremors and difficulty initiating movement.

Research has shown that the substantia nigra is the part of the brain that has the greatest number of mutations in mtDNA, and the mitochondria of patients with Parkinson’s disease exhibit several deficiencies. 7

Other studies in rats have shown a dose-dependent increase in free radicals in the mitochondria when the animals were administered L-dopa, the precursor to dopamine that is the primary drug therapy for Parkinson’s patients.8 These studies were the first indication that perhaps increasing the amount of a substance that we think is deficient might not be the answer.

Research into mitochondrial dysfunction in Parkinson’s disease has raised serious questions regarding the conventional use of L-dopa in the treatment of the disorder. L-dopa is prescribed in conventional medicine for its ability to improve the symptoms of Parkinson’s (at least temporarily), but it does not improve the underlying disease pathology. There is growing evidence that L-dopa might actually aggravate some of the underlying causes of Parkinson’s disease. In fact, it’s well known that L-dopa therapy eventually loses its effect, and the symptoms return even worse than before. As such, it might be time to reconsider the costs and benefits of L-dopa therapy.

The mitochondria of Parkinson’s patients also exhibit some inhibition of activity, although relatively milder than that seen in Alzheimer’s, along with a relative deficit of alpha-ketoglutarate dehydrogenase complex (KGDHC), a key enzyme found in the mitochondrial matrix. KGDHC produces nicotinamide adenine dinucleotide (NADH), an electron transporter molecule critical for cellular respiration (and thus mitochondrial function) that is significantly depleted in some brain regions of Parkinson’s patients.9

Interestingly, reductions in KGDHC levels have been noted in the cortex of Alzheimer’s patients as well.

M. Flint Beal, a prominent neurologist and professor of neuroscience at Cornell University, has spent years proving that CoQ10 has neuroprotective properties that might help diseases such as Parkinson’s and Huntington’s, and a growing body of scientific evidence supports his hypothesis.

His research team demonstrated that CoQ10 administration to middle-aged and old rats could restore levels of the nutrient to those of younger rats. The results showed that CoQ10 levels rose by 10-40 percent in the mitochondria of the cerebral cortex of the brain, where most higher thought occurs. 10

In a later study of mice, oral supplementation with CoQ10 slowed down the toxic effects of a poison that is known to cause a Parkinsonian syndrome in animals. After some weeks of exposure to the Parkinson’s-inducing chemical, dopamine concentrations and dopaminergic axon density in the area surrounding the substantia nigra fell in all the mice tested, but the levels in mice pretreated with CoQ10 were much higher (37 percent and 62 percent higher, respectively) compared to those only given the poison, confirming that a bioenergetic deficit is a component of the disease.11

Mitochondria: the powerpacks of the cell

Mitochondria are the powerhouses, or energy factories, of the cell. They are ‘organelles’ (specialized structures like microscopic organs within every cell) that act like a cellular digestive system to take in nutrients, break them down and create energy the cell needs to function.

This process of creating energy is known as cellular respiration, and most of the chemical reactions involved in cellular respiration take place in the mitochondria.

The mitochondria are very small, yet are evolved perfectly to maximize their hard work – they even have their own DNA, called mitochondrial or mtDNA, that encodes the specialized proteins needed for cellular respiration to occur. Each cell contains hundreds to several thousand mitochondria. The number depends on what the cell needs to do. For example, mitochondria are especially plentiful in heart and skeletal muscle (which require large amounts of energy for mechanical work) and in most organs (such as the pancreas, with its biosynthesis of insulin, and the liver, where detoxification takes place), including, particularly, the brain (where tremendous amounts of energy are required by nerve cells).

How brain signaling uses energy

The network of neurons throughout the body controls thoughts, movements and all of our senses by sending and receiving a variety of neurotransmitters (brain-signaling chemicals) at communication points between the cells called synapses. These neurotransmitters are released from tiny protrusions aligned along a neuron’s axon, called presynaptic boutons, and then bind to receptors on
the membrane of a neighboring cell.

But this isn’t a one-size-fits-all process – brain cells communicate with one another at a range of strengths or intensities. Sometimes they speak loud and clear, but other times they whisper or mumble.

For years, scientists questioned why and how neurons change their intensity so frequently. A study by researchers at the National Institutes of Health published in the summer of 2013 showed that rapidly moving mitochondria emit bursts of energy, which appeared to regulate neuronal communication.1

The presynaptic boutons help control the strength of the signals sent by regulating the quantity of neurotransmitters released as well as the manner in which they are released. The production of neurotransmitters, their packaging and release, and the reception or removal of these chemicals all require energy.

Previous studies showed that mitochondria can move rapidly along axons, dancing, in a sense, from one bouton to another.

The NIH researchers took this observation a step further by showing that these moving mitochondria might control the strength of the signals sent from boutons. They used advanced techniques to watch mitochondria move between boutons while neurotransmitters were being released, and found that boutons only sent consistently strong signals when mitochondria were nearby. When the mitochondria were absent or moving away from boutons, their signal strength fluctuated.

These results suggest that the presence of stationary mitochondria at synapses improves the stability and strength of the nerve signals. Previously, it had been shown that about one-third of all mitochondria in axons move about; the rest are stationary.2

Nerve cell communication is obviously tightly controlled by highly dynamic events occurring at numerous synapses. This discovery will be highly valuable in understanding how mitochondria are involved in not just neurodegenerative disease but any neurological condition in which nerve cell signaling is altered, such as depression and ADHD.

The great protector: pyrroloquinoline quinone (PQQ)

Early in 2010, researchers discovered that pyrroloquinoline quinone (PQQ), an enzyme co-factor now considered an unidentified B vitamin, not only protected mitochondria from oxidative damage, it also stimulated the growth of new mitochondria.1

A number of physiological properties have been attributed to PQQ, including protection of nerve cells, promotion of nerve growth and mitochondrial biogenesis. There is strong evidence PQQ might play an important role in pathways important to cell signaling.

Studies in animals have shown that PQQ protects nerve cells from degeneration and damage, and even promotes the growth of nerve cells and helps form new synapses (connections) between nerve cells, which are critical for memory. Now, preliminary research in humans is beginning to confirm the potential health benefits of PQQ.

Studies also suggest that PQQ might have anti-inflammatory effects, be an effective neuroprotectant (reducing brain damage during stroke and protecting brain cells against excitotoxic overstimulation), and be a stimulator of nerve growth factor, a key protein involved in the growth and survival of nerve cells).2

Suggested daily dosage: In one study, 20 mg PQQ taken orally every day improved short-term memory, attention, concentration, information identification and processing ability in healthy adults. The effects were greatly enhanced when CoQ10 supplements were added.

Brain boosters

CoQ10

Coenzyme Q10 (CoQ10), a vitamin-like molecule that is naturally present in just about every single cell in our body, is an antioxidant, a membrane stabilizer and a vital component of the energy production process in mitochondria. It also has neuroprotective effects.

Studies have shown that CoQ10 can increase the number of mitochondria in the brain and protects animals from both poison- and gene mutation-induced neurodegeneration.1

Although we do get small amounts of CoQ10 from our food, it amounts to only a few milligrams daily – not nearly enough for our bodies to benefit clinically, and supplementation becomes increasingly important the older we get.

Researchers are actively developing new delivery systems to improve the effectiveness of CoQ10.2 Oil-based formulations (typically softgels) are thought to be more readily absorbed by the body, and water-dispersible liposomal or pre-emulsified formulations are even better.

Ubiquinol (reduced CoQ10) seems to offer much better absorption than ubiquinone (oxidized CoQ10), and water-soluble (solubilized) ubiquinol is even better absorbed still.

Suggested daily dosage: For neurological conditions, from 600-3,000 mg, taken in smaller doses throughout the day with food

D-Ribose

This simple five-carbon sugar is important for energy synthesis (as a structural component of ATP, the molecule responsible for storing energy). In the 1980s, researchers discovered that with supplements of D-ribose, when given prior to or immediately after ischemia in the heart, energy-deficient hearts could recover their cellular energy levels.3

Suggested daily dosage: from 3 -5 g

L-Carnitine

L-carnitine (levocarnitine), a naturally occurring compound found in all mammalian species, transports fats into the mitochondria to produce ATP.

Dietary L-carnitine intake is largely achieved via consumption of animal-based products, including red meats, poultry, fish and dairy products, while negligible quantities are present in plant-derived foods.

The standard omnivorous diet provides 6-15 millimoles per kilogram a day, and the standard vegetarian diet providing less than 1 millimole per kilogram a day.

L-carnitine requires other nutrients, including iron, vitamin C, oxygen, pyridoxal-5-phosphate (the biologically active form of vitamin B6), and vitamin B3 in order to be properly synthesized.

Suggested daily dosage: 500-2,000 mg

Magnesium

Magnesium is a critical cofactor in over three hundred biochemical reactions in the body, including the production of ATP.

Mitochondria act as our intracellular magnesium stores, and much of the magnesium in the body is found bound to ATP, which helps stabilize the molecule and make it usable by the body.

Suggested daily dosage: 400-800 mg

Alpha-lipoic acid

Alpha-lipoic acid (ALA), an antioxidant found in mitochondria, can be manufactured by the body for its metabolic functions under optimum circumstances, but additional ALA provided by supplements allows it to function as both a water- and fat-soluble antioxidant.

The body can only use one form, called the R(+) form, which is sold refrigerated (and should be stored in the fridge at home). Avoid exposing ALA to any sources of heat (such as leaving the bottle in your car on a hot summer day).

Suggested daily dosage: 300-600 mg

Creatine

The human body creates creatine from the amino acids methionine, glycine, and arginine. On average, a person’s body contains about 120 grams of creatine stored in the form of creatine phosphate (also known as phosphocreatine). Certain foods (such as beef and fish) have a relatively high creatine content.

A growing number of studies have found that creatine can protect the brain from neurotoxic agents and certain forms of brain injury. Studies have also found creatine to be highly neuroprotective against various neurotoxic agents.4

Suggested daily dosage: 2-25 g, depending on body weight (0.1 g/kg body weight)

Resveratrol and pterostilbene

Scientists have now discovered another close relative of resveratrol, the compound found in red wine widely touted for its benefits to brain health, called pterostilbene (pronounced “tare-o-STILL-bean”).

Pterostilbene is mainly found in blueberries, which contain large quantities, as well as in grapes and the bark of the Indian kino tree (used for centuries in traditional Ayurvedic medicine), and seems to have a synergistic effect with pterostilbene on the brain.5

Pterostilbene produces beneficial changes including up-regulating specific brain proteins associated with improved memory. Of course, many of these benefits relate back to the humble mitochondria.

Suggested daily dosage: 150-500 mg resveratrol; 100-500 mg pterostilbene

Adapted from Mitochondria and the Future of Medicine by Lee Know, ND (Chelsea Green Publishing, 2018)

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How brain signaling uses energy

The great protector: pyrroloquinoline quinone (PQQ)

Brain boosters

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