Tau proteins carry out very important functions in the brain. Especially in brain cells or neurons. They are akin to spot welds on cellular scaffolds that form tracks that shuttle other vital molecules to and fro within nerve cells. Their activity is governed by other cellular communicators called "phosphate groups." They attach to the tau proteins and enable them to perform their unique task. However, under certain circumstances the assembly line that regulates where and how many phosphate groups are attached runs amok. Under these conditions more and more phosphate groups are attached end to end, and instead of enhancing the activity of tau proteins, they create problems.

One type of problem with these "hyper-phosphorylated" tau proteins is that they accumulate and form masses called neuro-fibrillary tangles (NFTs). These NFTs are a purported cause of Alzheimer disease.

Based on these observations, findings made by researchers at McGill University in Canada offer new hope for the early diagnosis and treatment of Alzheimer disease. In a study published in the Journal of Biological Chemistry on May 15, they reported that the addition of a single phosphate group to a specific amino acid (protein building block) in tau proteins is a principal cause of Alzheimer disease.

Normal tau proteins only contain three or four phosphate groups, but the abnormal tau proteins can contain 20 to 25 additional phosphates. What the McGill scientists discovered was that the addition of a single phosphate group to a certain amino group (Serine 202) was the primary culprit responsible for the changes seen in Alzheimer disease.

This is important for two reasons. The first is that brain scans could be developed to identify that change. The second is that the enzyme that adds the phosphate to that specific amino group could become the target for drug therapy. Together, these suggest that early diagnosis and treatment may be at hand!

 

Evidence is accumulating that over-eating -- frequently associated with the development of obesity and diabetes -- is intimately associated with the development of memory disorders and more ominous conditions such as Mild Cognitive Impairment and even neurodegenerative disorders such as Alzheimer disease. For these reasons, I was interested to see a recent posting describing new research that investigated the link between dietary composition and appetite.

Researchers measured the levels of insulin and GLP-1 (short for Glucagon-like peptide-1) following two different types of meal. The meals differed in what is called GI (Glycemic Index). GI is a parameter that describes how various types of carbohydrate foods affect the body's blood sugar levels in the hours following their ingestion. High GI carbohydrates (including bread, cakes, cookies and cornflakes) markedly elevate blood glucose levels following a meal. Low GI carbohydrates increase blood glucose levels much less when consumed. They include most vegetables and non-starchy fruits. Low GI carbohydrates are usually broken down and digested more slowly than high GI foods thus releasing sugar into the bloodstream more slowly.

A low GI diet is known to cause reduced appetite, but the precise mechanisms behind this effect were not known. To address this, Dr. Reza Norouzy and colleagues at King's College London looked at the impact of a single low versus high GI meal on gut hormone levels in twelve healthy volunteers. Each subject was given a medium grade GI dinner the night before, fasted and then was randomly provided either a low (46) or high (66) GI meal for breakfast. Blood samples were taken every thirty minutes for 150 minutes and blood levels of the gut hormone GLP-1 and insulin were measured.

Volunteers who consumed the low GI breakfast had GLP-1 levels that were 20% higher than those eating the high GI meal. They also had 38% lower insulin levels over the same time interval. It is known that GLP-1 potently decreases appetite. These studies show for the first time that a low GI meal elevates GLP-1 levels and these are associated with diminished appetite. This observation provides a physiological mechanism to explain how a low GI meal makes you feel fuller than a high GI meal.

This insight might be used to guide food choices that diminish appetite and (hopefully) help us all maintain optimal weight and brain function at any age.

 

Deterioration and loss of the microscopic connections between brain cells (referred to as synapses) underlies the memory loss and other mental dysfunction seen in Alzheimer disease. The culprit behind all of this damage and destruction is believed to be soluble beta amyloid fibrils. They bind to specific sites on nerve cell membranes (the outer coatings of the nerve cells) in the region of synaptic connections. In so doing, they trigger the production of inflammation and subsequent damage to the tiny nerve cell connections. As they are lost, the nerve cells become functionally disconnected and can't perform the computer-like computations that are the basis for every thought we have.

This information is not particularly new. However, the observation that a protective mechanism exists that can shield nerve cells from the beta amyloid toxins is. The exciting thing about this finding is that it can prevent the deleterious changes from happening before symptoms develop! The savior in all of this drama is the hormone insulin. It so happens that insulin in the brain prevents the binding of beta amyloid fibrils to the receptors they must interact with to cause damage to the synaptic connections.

The proposed mechanism behind the insulin protective effect is not one of insulin interfering with the binding of beta amyloid to its receptors, but the actual down-regulation, or reduction , in the number of beta amyloid binding sites on the nerve cell membranes. To cause this reduction in beta amyloid binding sites, insulin must first bind to insulin receptors on the same nerve cell and produce an insulin signal within the nerve cell. The end result of this complex process is the loss of beta amyloid binding sites in the synaptic region. Without the binding sites, beta amyloid is almost helpless.

The novel finding that insulin mitigates synaptic vulnerability suggests that mechanisms that enhance brain insulin signaling, which declines with aging and diabetes, could potentially slow the onset or development of Alzheimer disease. In brain cells grown in tissue culture (like growing bacteria in a Petrie dish), this observation was confirmed in two separate ways -- by directly adding insulin to nerve cells, and by adding a drug that improves insulin sensitivity (meaning when the insulin that was normally present binds to its receptor of the nerve cells, the response is enhanced). Both interventions improved insulin signaling and decreased inflammation and loss of synapses.

While these studies were done in tissue culture, there are other ways to enhance brain insulin signaling, which include calorie and carbohydrate restriction. These interventions were studied in mice who were placed on low calorie/low carb diets. The lead author in this study was Dr. Giulio Maria Pasinetti. Based on his findings, he noted, "Both clinical and epidemiological evidence suggest that modification of lifestyle factors such as nutrition may prove crucial to Alzheimer's disease management. This research, however, is the first to show a connection between nutrition and Alzheimer's disease neuropathy by defining mechanistic pathways in the brain and scrutinizing biochemical functions."

 

When we are young and are eating a healthy diet, there are minimal fluctuations in the level of blood glucose. This is not very exciting because blood glucose doesn't get too high or too low. But that's exactly how things should work. However, as we get older the body is not as efficient at regulating and controlling blood glucose. As a result, the swings get bigger -- too high at some times and too low at others. What we eat can have the same effect. A sugary meal or snack can send blood glucose sky rocketing minutes after the meal ... and then plummeting down below normal an hour later. As a matter of fact, this is a fairly common occurrence today and is easily observed at work. Look around at your coworkers an hour or so after lunch. What do you see? Most of them are ready for a nap. They are sluggish and inefficient. This is what happens when glucose levels fall. Why? Because the brain burns glucose and when it's main fuel supply is not available, it suffers. Mental brownouts occur, energy levels fall and mental torpor is the result. Clearly, these dramatic glucose fluctuations are not good for the brain. This is what I call the Roller Coaster Effect.

Most of us think immediately about diabetes when a doctor mentions blood sugar problems. Now it appears that memory loss and Alzheimer disease might  be just around the corner. This is due to the Roller Coaster Effect. We have just discussed why so many of us feel sleepy and just not very sharp after lunch. Let's look at a more extreme example of the same thing. We all know people who were diagnosed with childhood diabetes (Type 1 diabetes, or "insulin-dependent" diabetes) because they are always checking their glucose level and injecting themselves with insulin shots throughout the day. One of the major complications this group of individuals experience is low blood glucose -- or hypoglycemia. When this occurs they can feel jittery, light-headed or even sleepy. If the condition goes uncorrected, and the blood sugar becomes quite low, they think more slowly and may even become comatose. This is related to low blood glucose and the resultant lack of an energy supply for the brain. It causes power outages and loss of mental function. These periods of low glucose represent the dips in the roller coaster ride.

Brain researchers have recently discovered a link between brain health and high blood glucose levels. At first, this may seem counterintuitive because with high glucose levels one would think that the brain would be happy. However, such appears not to be the case. Over the past couple of years, researchers have starting connecting the link between elevated blood sugar and and elevated risk for Alzheimer disease. That is now a well-known fact. More recently, a study presented by Swedish scientists showed that simply experiencing higher than normal blood sugar levels may be enough to potentially lead to Alzheimer disease.

The number of individuals this affects is not trivial. More than 40 million Americans fall into this category. They are in the "pre-diabetic" group. It is well known that obesity is a risk factor for memory loss and more serious conditions. Now we can add to this the Roller Coaster Effect -- that is, poor control of blood sugar.

What concerns many public health officials about these recent findings is that Alzheimer disease is expected to increase fourfold in the next four decades as baby boomers live longer. Now, in addition to living longer, we have a huge pool of aging Americans with increasingly more abnormal blood glucose control, another potent risk factor for these afflictions. It now appears that aging and poor glucose control are going to dramatically magnify the numbers of Americans developing Alzheimer disease. As a result, many researchers are worried that Alzheimer's will swamp health care systems worldwide.

More recently, investigators at Columbia University found that even modest swings in blood sugar levels can lead to memory loss severe enough to affect everyday function. These sugar fluctuations can be subtle enough not to even be considered a disease state!

One of the major processing regions for memory function is called the hippocampus. Subjects with abnormal blood glucose levels were found to have decreased hippocampal volumes compared to subjects with normal blood glucose levels.

To make matters worse, other researchers have noted an association with poor blood glucose control and the buildup in the brain of sticky clumps of protein that lead to the development of senile plaques -- the hallmarks of Alzheimer disease.

How can blood sugar be controlled? Eating properly and  exercising! The same recommendations that insure a healthy body. So get started now and avoid the Roller Coaster Effect!

 

The term "neurodevelopmental disorders" encompasses a large group of neurological disorders that become evident during periods of brain maturation. They frequently share complex neurological features including various learning disabilities and complex behavioral features. These disorders become evident in early childhood and tend to persist into the adult lifespan. Included in this constellation of disabilities are autism, ADD (attention deficit disorder) and pervasive developmental disorder. It is believed they are caused by genetic mutations and environmental factors.

Alterations in the configuration, wiring and connectivity of the developing brain are key contributors. There are specific periods during brain formation where certain influences can produce significant functional alterations that might be insignificant if they first occurred in adults.

Fetal and perinatal programming experiments in animals have documented persistent abnormalities in glucocorticoid receptors and signaling in offspring related to variations in maternal care that engender the perception of stress in the offspring. This alters stress responsivity -- changes that persist into adulthood. Many of the mutations that cause developmental disorders disrupt genes that are also expressed in the adult brain. This insight is significant because in addition to the developmental affects they cause in the brains of young children, it is possible that altered function of these genes may produce additional effects in adulthood (additive to those changes in brain wiring produced during the formative years).

This very possibility has been investigated in animal models of human neurodevelopmental disorders. Results suggest that persistent expression of the genes that caused the disorder to manifest initially during childhood may contribute to cognitive or behavioral problems in adults. These studies support the concept that treating the disrupted molecular mechanisms in adults might result in functional improvement. It has even been speculated that biochemical improvement of the underlying genetic defects may produce metabolic changes that allow adult neuroplasticity mechanisms to compensate for certain of the characteristic developmental problems.

The animal studies have investigated models of neurofibromatosis, a disorder in which neurological symptoms including attentional issues, deficits in executive function and learning disabilities are produced. One of the effects of the NF (neurofibromatosis) gene is to interfere with specific cellular signaling pathways. This results in the activation of Ras-signaling pathways.

There are pharmacological interventions that can reduce the isoprenylation of Ras, thereby tending to normalize this vital signaling pathway. HMG-CoA reductase inhibition with the drug lovastatin (a cholesterol-lowering drug) is one such intervention. Notably, short pharmaceutical treatment of animals with NF using lovastatin reduces the cognitive impairments in these animals while having no effects on control animals. When tested in humans, a 12 week treatment with simvastatin improved performance on a neuropsychological test. Moreover, the treatment protocol had the most robust beneficial effect on patients with the worst baseline status.

Similar benefits using this molecular approach have been observed in animal models of other neurodevelopmental disorders including Down's syndrome, Rubenstein-Taybi syndrome (another genetic disorder that is characterized by intellectual disorders, and specific physical features such as broad thumbs and and toes), Tuberous sclerosis, Fragile X syndrome (associated with learning disabilities, autism, ADD (attention deficit disorder) and epilepsy) and Rett syndrome.

The obvious conceptual epiphany in this approach is the ability to improve functional indicators in adults with neurodevelopmental disorders long after the brain has matured. Many of these disorders are common and disabling. They also have limited treatment options.

 

In BACE-ball and your brain I discussed how energy shortages in the brain tend to increase the activity of an enzyme (BACE1) that speeds up the activation of APP (amyloid precursor protein). This increases the formation of A-beta (for beta amyloid), which is associated with the development of Alzheimer disease. Thus, energy brownouts are to be avoided at all costs. Dr. Robert Vassar, the lead author of this insightful article, linked deficits in energy generation in the brain with the development of narrowing of the arteries to the brain.  Oxygen and nutrients such as the major brain fuel glucose are delivered to nerve cells via the circulatory system. When blood flow is restricted, these vital compounds don't get where they need to go and brain cells suffer. One result is impaired energy generation and activation of BACE1.

Another interesting paper that relates to this very issue was recently published in the medical journal Brain Research (1226 (2008): 209-219). It further investigates the connection between power brown outs in the brain and A-beta formation. The investigations were performed in very old dogs who spontaneously produce A-beta in their brains.

The authors noted that localized declines in cerebral glucose metabolism are an early and progressive feature of Alzheimer disease. They state that such declines occur long before symptoms develop and, as such, offer a window of time for medical intervention. Medium chain triglycerides (MCTs) are rapidly turned into ketone bodies in the liver and ketones are used efficiently in the brain as an optional fuel source. Noting this, they provided a nutritional product (MCT oil) that can generate this alternative fuel (ketones) for the brain when glucose is in short supply or is not being used efficiently. In their study, dogs were supplemented with MCT oil for several months and brain metabolism was subsequently investigated.

They documented that aged dogs receiving the MCT therapy showed markedly improved mitochondrial (mitochondria are the small intra-cellular inclusions that generate energy) function. The effect was most prominent in the parietal lobe region. This is where early decreases in glucose use tends to occur in patients with Alzheimer disease. APP levels also decreased. There was also a trend towards a decrease in total A-beta in the parietal lobes of the treated dogs.

What this tells us is that energy generation was improved and with it APP and A-beta levels fell. These results are consistent with the hypothesis that brain cell energy failure (an inciting cause of Alzheimer disease) can trigger the buildup of A-beta, which ultimately leads to neurodegeneration. Furthermore, they suggest that by supplying another fuel source for the neurons to use, the process can be reversed with beneficial results. The take home message might be that for anyone at risk for such diseases, that chronic supplementation with MCT oil might be a prudent preventative intervention.

 

Alzheimer Disease (AD) and a host of other so-called neurodegenerative diseases such as Parkinson Disease and Lou Gehrig Disease (also called ALS -- for Amyotrophic Lateral Sclerosis -- a wasting disease that tends to affect motor nerves and secondarily muscle function in the arms and legs as well as the swallowing and breathing muscles) have been refractory to treatment largely because the exact cause of each of these devastating disorders is unknown. They have been the subject of intense research to no avail -- that is until recently. A remarkable paper was recently published in the medical journal Neuron. The lead author was Dr. Robert Vassar from Northwestern.

The purportedly toxic compound that builds up in the brains of persons afflicted with AD is called beta-amyloid (A-beta for short). It is produced by the cleavage of amyloid-beta precursor protein (APP) by the action of beta-site APP cleaving enzyme 1 (BACE1). This accelerates the buildup of A-beta. The level and activity of BACE1 are increased in the brains of AD patients. This led to the idea that the chronic increase in BACE1 in the brain may contribute to the development of AD.

This is not of much help to those persons at risk for this devastating disease unless something can be done about it. From a pharmaceutical perspective, such hope is on a distant horizon. However, an interesting observation might provide a clue as to what leads these sticky amyloid fibrils to form and aggregate. This insight was identified by the application of several metabolic manipulations that each decreased energy generation in neurons. One involved impairing the electron chain, which is the main conveyor belt that turns food into energy. Another was a potent inhibitor of an enzyme in the glucose metabolic pathway, while yet another manipulation involved administering an overdose of insulin to the lab animal. This latter model of energy impairment caused cerebral brownouts by causing blood glucose levels to fall to markedly subnormal levels. This prevented the neurons from accessing their primary fuel -- glucose.

The common thread in each of these models was an increase in BACE1 and the accumulation of A-beta.

The researchers suggested that physiologic changes that increased blood flow to the brain, which would deliver more oxygen and more glucose, would enhance energy production and lessen A-beta via a beneficial effect on BACE1. What they omitted to mention is that many neuroscientists are starting to refer to AD as Type 3 diabetes because of the presence of a similar inability of the brain to take up and metabolize glucose as that which exits in the tissues of the body in Type 2 diabetes (the type generally associated with obesity). This is significant because diabetes is a metabolic disorder that responds to various lifestyle factors that stabilize blood sugar swings and enhance insulin sensitivity. These same interventions would be expected to enhance cerebral glucose metabolism and act to alleviate energy shortages, BACE1 activation and accumulation of A-beta, the alleged culprit behind the initiation of AD.

These findings are consistent with a reversible etiology of one of the primary modern day medical scourges. One that we may ameliorate by making appropriate lifestyle choices that are easily within our control.

By David Derbyshire

Two months ago Clem Fennell was fading fast.

The victim of an aggressive type of dementia, the 57-year-old businessmen was unable to answer the phone, order a meal or string more than a couple of words together.

In desperation, his family agreed to try a revolutionary new treatment - a bizarre-looking, experimental helmet devised by a British GP that bathes the brain in infra-red light twice a day.

To their astonishment, Mr Fennel began to make an astonishing recovery in just three weeks.

Dr Gordon Dougal, a GP from County Durham, treated dementia patient Clem Fennell with his infra-red device

"My husband, Clem, was fading away. It is as if he is back" said his wife Vickey Fennell, 55. "His personality has started to show again. We are  absolutely thrilled."

While the helmet has yet to be proven in clinical trials, the family say the effects of the 10 minute sessions are incredible. Mr Fennell can now hold conversations and go shopping unaccompanied.

The treatment is the brainchild of Dr Gordon Dougal, a County Durham GP. He believes the device could eventually help thousands of dementia patients.

"Potentially, this is hugely significant," said Dr Dougal, who is based in  Easington, County Durham and is a director of Virulite, a medical research company.

Developed with Sunderland University, the helmet has 700 LED lights that  penetrate the skull. They are thought to be the right wavelength to stimulate the growth of brain cells, slowing down the decline in memory and brain function and reversing symptoms of dementia.

Clem Fennell - the head of a family engineering firm in Cincinnati, Ohio - travelled to the UK after neurologists told him nothing could stop the decline of his dementia. The family's friends had seen  a report about the helmet on CBS.

"Honestly I can tell you that within ten days, the deterioration was stopped,  then we started to see improvements," said Mrs Fennell,  from North Kentucky. "He started to respond to people more quickly when they talked to him." 

Three weeks later, the father of two is still making gradual improvements.

His daughter, 22-year-old Maggie said: "When we go to the restaurant  we usually have to order his meals for him, now he can order for himself." 

"Now we are okay about letting him go to the bank or the  post office but he would not have been able to do that three weeks ago.

Mr Fennell could hardly string two words together. But since using the infra-red helmet, he can hold a conversation.

"Dr Dougal has been a godsend to our family. There was nothing anyone could do  to help Clem until now." 

It is too soon to say whether Dr Dougal's invention could help other sufferers. The symptoms of Alzheimer's disease and dementia can vary from day to day - and relapses are not unusual. And not all patients may benefit from the treatment.

Dr Dougal stressed that a full, clinically controlled trial would be needed  before his anti-dementia helmet could be licensed for public use. A trial of 100 patients is expected to start later this year.

"I made it clear to the Fennells that I didn't know for a fact  whether it would work or not, but the results are good," said Dr Dougal.

"He was monosyllabic when I first saw him, but if I ring up now he will answer  the phone. He didn't have the verbal skills to do that three weeks ago." 

The Fennells have been told they can take the prototype helmet back to the US  with them so they can continue the treatment at home.

Commercial versions of the helmet will include 700 LEDs and cost around £10,000.

The Alzheimer’s Society said: "’A treatment that reverses the effects of dementia rather than just temporarily halting its symptoms could change the lives of the hundreds of thousands of people who live with this devastating condition.

‘Non-thermal near infra-red treatment for people with dementia is a potentially interesting technique. We look forward to further research to determine whether it could help improve cognition in humans. Only then can we begin to investigate whether near infra-red could benefit people with dementia.’

One in three people will end their lives with a form of dementia. Around 700,000 suffer from dementia - with more than half having Alzheimer's disease.