Summary: A novel, custom-built microscope allowed researchers to track the activity of a single neuron across the entire visual cortex.
Source: HHMI
Using a custom-built microscope to peer into the mouse brain, scientists have tracked the activity of single neurons across the entire visual cortex.
These recordings, made in the tenths of seconds after the animals saw a cue on a screen, expose the complex dynamics involved in making sense of what the eyes see.
In an unprecedented combination of breadth and detail, the results describe the behavior of more than 21,000 total neurons in six mice over five days, Howard Hughes Medical Institute Investigator Mark Schnitzer’s team reports in the journal Nature on May 18, 2022.
His team is the first to get a glimpse of individual cells’ activity occurring at the same time throughout eight parts of the brain involved in vision.
“People have studied these brain areas before, but prior imaging studies did not have cellular resolution across the entire visual cortex,” says Schnitzer, a neuroscientist at Stanford University.
The work highlights the dramatic sequence of events that unfolds in the brain from the instant it receives messages from the eyes until it decides how to respond to that sight. The researchers’ far-reaching but fine-grained imaging approach made it possible for them to collect an “incredible” set of data, says Tatiana Engel, a computational neuroscientist at Cold Spring Harbor Laboratory who was not involved in the study.
While previous studies have already explored aspects of this process, such as variations in single neurons’ activity and coordination between larger brain areas, this research offers an expansive new view, she says. “The scale on which they’re able to address these topics is very impressive.”
When the eyes see an image, they send electrical signals that end up in the visual cortex, the wrinkly outer layer of the brain near the back of the head. There, the signals trigger a flurry of activity as neurons work together to register an image, evaluate it, and decide how to respond.
To capture activity across the visual cortex, Schnitzer and his colleagues built a custom microscope with a wide field of view. Their system could also capture detail at a resolution of a few thousandths of a millimeter, small enough to detect single neurons. By using genetically engineered mice with neurons that fluoresce when sending signals, the team could watch these cells’ activity.
During the team’s experiments, mice had to make a choice based on one of two visual cues. One prompted the animals to lick a spout for some sugar water, the other cue indicated “don’t lick.” The mice performed many of these tests over five days.
With recordings made from the mice’s brains, the team posed a simple question: What happens in the brain when we see something? Their results lay out this invisible process at a time-resolution of fractions of a second and uncover surprising nuances.
The work highlights the dramatic sequence of events that unfolds in the brain from the instant it receives messages from the eyes until it decides how to respond to that sight. Image is in the public domain
Scientists, for example, already knew that individual neurons behave variably when responding to visual signals conveyed by the eyes. But Schnitzer’s team’s experiments revealed a pattern to this unreliable behavior. That pattern could make it easier for brain areas receiving the neurons’ signals to make sense of them and accurately interpret the visual scene.
The researchers also documented how, about 200 milliseconds after the visual cue appeared, the animals switched mental gears: messages from the eyes prompted a massive rearrangement in different brain areas’ activity. About 500 milliseconds afterward, this surge subsided and the activity became more stable and recognizable.
Next, roughly 600 milliseconds later, another signal emerged, activating all eight of the brain areas. That signal encoded the animal’s decision to stay still or go for the sugar water. The researchers learned how to read the signal, so they could predict which response the mouse would make.
“It’s fascinating how much the brain is doing in the immediate moments after the eyes see the stimulus,” Schnitzer says.
And it could also be the kindling sparking Parkinson’s and other neurodegenerative
For decades researchers have focused their attacks against Alzheimer’s on two proteins, amyloid beta and tau. Their buildup in the brain often serves as a defining indicator of the disease. Get rid of the amyloid and tau, and patients should do better, the thinking goes.
But drug trial after drug trial has failed to improve patients’ memory, agitation and anxiety. One trial of a drug that removes amyloid even seemed to make some patients worse. The failures suggest researchers were missing something. A series of observations and recently published research findings have hinted at a somewhat different path for progression of Alzheimer’s, offering new ways to attack a disease that robs memories and devastates the lives of 5.7 million Americans and their families.
One clue hinting at the need to look further afield was a close inspection of the 1918 worldwide flu pandemic, which left survivors with a higher chance of later developing Alzheimer’s or Parkinson’s. A second inkling came from the discovery that the amyloid of Alzheimer’s and the alpha-synuclein protein that characterizes Parkinson’s are antimicrobials, which help the immune system fight off invaders. The third piece of evidence was the finding in recent years, as more genes involved in Alzheimer’s have been identified, that traces nearly all of them to the immune system. Finally, neuroscientists have paid attention to cells that had been seen as ancillary—“helper” or “nursemaid” cells. They have come to recognize these brain cells, called microglia and astrocytes, play a central role in brain function—and one intimately related to the immune system.
All of these hints are pointing toward the conclusion that both Alzheimer’s and Parkinson’s may be the results of neuroinflammation—in which the brain’s immune system has gotten out of whack. “The accumulating evidence that inflammation is a driver of this disease is enormous,” says Paul Morgan, a professor of immunology and a member of the Systems Immunity Research Institute at Cardiff University in Wales. “It makes very good biological sense.”
The exact process remains unclear. In some cases the spark that starts the disease process might be some kind of insult—perhaps a passing virus, gut microbe or long-dormant infection. Or maybe in some people, simply getting older—adding some pounds or suffering too much stress could trigger inflammation that starts a cascade of harmful events.
This theory also would explain one of the biggest mysteries about Alzheimer’s: why some people can have brains clogged with amyloid plaques and tau tangles and still think and behave perfectly normally. “What made those people resilient was lack of neuroinflammation,” says Rudolph Tanzi, a professor of neurology at Harvard Medical School and one of the leaders behind this new view of Alzheimer’s. Their immune systems kept functioning normally, so although the spark was lit, the forest fire never took off, he says. In Tanzi’s fire analogy, the infection or insult sparks the amyloid match, triggering a brush fire. As amyloid and tau accumulate, they start interfering with the brain’s activities and killing neurons, leading to a raging inflammatory state that impairs memory and other cognitive capacities. The implication, he says, is that it is not enough to just treat the amyloid plaques, as most previous drug trials have done. “If you try to just treat plaques in those people, it’s like trying to put out forest fire by blowing out a match.”
Lighting the Fire
One study published earlier this year found gum disease might be the match that triggers this neuroinflammatory conflagration—but Tanzi is not yet convinced. The study was too small to be conclusive, he says. Plus, he has tried to find a link himself and found nothing. Other research has suggested the herpes virus could start this downward spiral, and he is currently investigating whether air pollution might as well. He used to think amyloid took years to develop, but he co-authored a companion paper to the herpes one last year, showing amyloid plaques can literally appear overnight.
It is not clear whether the microbes—say for herpes or gum disease—enter the brain or whether inflammation elsewhere in the body triggers the pathology, says Jessica Teeling, a professor of experimental neuroimmunology at the University of Southampton in England. If microbes can have an impact without entering the brain or spinal cord—staying in what’s called the peripheral nervous system—it may be possible to treat Alzheimer’s without having to cross the blood–brain barrier, Teeling says.
Genetics clearly play a role in Alzheimer’s, too. Rare cases of Alzheimer’s occurring at a relatively young age result from inheriting a single dominant gene. Another variant of a gene that transports fats in brain cells, APOE4, increases risk for more typical, later-onset disease. Over the last five years or so large studies of tens of thousands of people have looked across the human genome for other genetic risk factors. About 30 genes have jumped out, according to Alison Goate, a professor of neurogenetics and director of the Loeb Center for Alzheimer’s Disease at Icahn School of Medicine at Mount Sinai in New York City. Goate, who has been involved in some of those studies, says those genes are all involved in how the body responds to tissue debris—clearing out the gunk left behind after infections, cell death and similar insults. So, perhaps people with high genetic risk cannot cope as well with the debris that builds up in the brain after an infection or other insult, leading to a quicker spiral into Alzheimer’s. “Whatever the trigger is, the tissue-level response to that trigger is genetically regulated and seems to be at the heart of genetic risk for Alzheimer’s disease,” she says. When microglia—immune cells in the brain—are activated in response to tissue damage, these genes and APOE get activated. “How microglia respond to this tissue damage—that is at the heart of the genetic regulation of risk for Alzheimer’s,” she says.
But APOE4 and other genes are part of the genome for life, so why do Alzheimer’s and Parkinson’s mainly strike older people? says Joel Dudley, a professor of genetics and genomics, also at Mount Sinai. He thinks the answer is likely to be inflammation, not from a single cause for everyone but from different immune triggers in different individuals.
Newer technologies that allow researchers to examine a person’s aggregate immune activity should help provide some of those answers, he says. Cardiff’s Morgan is developing a panel of inflammatory markers found in the blood to predict the onset of Alzheimer’s before much damage is done in the brain, a possible diagnostic that could point to the need for anti-inflammatory therapy
Like Threads
A similar inflammatory process is probably also at play in Parkinson’s disease, says Ole Isacson, a professor of Neurology at Harvard Medical School. Isacson points to another early clue about the role of inflammation in Parkinson’s: people who regularly took anti-inflammatory drugs like ibuprofen developed the disease one to two years later than average. Whereas other researchers focused exclusively on genetics, Isacson found the evidence suggested the environment had a substantial impact on who got Parkinson’s.
In 2008–09, Isacson worked with a postdoctoral student on an experiment trying to figure out which comes first in the disease process: inflammation or the death of dopamine-producing neurons, which make the brain chemical involved in transmitting signals among nerve cells. The student first triggered inflammation in the brains of some rodents with molecules from gram-negative bacteria and then damaged the neurons that produce dopamine. In another group of rodents, he damaged the neurons first and then introduced inflammation. When inflammation came first, the cells died en masse, just as they do in Parkinson’s disease. Blocking inflammation prevented their demise, they reported in The Journal of Neuroscience.
Other neurodegenerative diseases also have immune connections. In multiple sclerosis, which usually strikes young people, the body’s immune system attacks the insulation around nerve cells, slowing the transmission of signals in the body and brain.
The spinal fluid of people with MS include antibodies and high levels of white blood cells, indicating the immune system is revved up—although it is not clear whether that immune system activation is the cause or result of MS, says Mitchell Wallin, who directs the Veterans Affairs Multiple Sclerosis Centers of Excellence. People with antibodies to the Epstein–Barr virus in their systems, especially if they caught the virus in late adolescence or early adulthood run a higher risk of developing MS—supporting the idea that an infection plays a role in MS.
Thanks to newer medications and improvements in fighting infections, people with MS are now living longer. This increased longevity puts them at risk for neurological diseases of aging, including Alzheimer’s and Parkinson’s, Wallin says. Lack of data has left it unclear whether people with MS are at the same, higher or lower risk for these diseases than the general population. “How common it is, we’re just starting to explore right now,” Wallin says.
Coming Soon?
It will be years before the concept of a neuroinflammatory can be fully tested, but there are already some relevant drugs in development. One start-up, California-based INmune Bio, recently received a $1-million grant from the Alzheimer’s Association to advance XPro1595, a drug that targets neuroinflammation. The company is beginning its first clinical trial this spring, treating 18 patients with mild to moderate-stage Alzheimer’s who also show signs of inflammation. The company plans to test blood, breath by-products and cerebral spinal fluid as well as conduct brain scans to look for changes in inflammatory markers. That first trial will just explore if XPro1595 can safely bring down inflammation and change behaviors such as depression and sleep disorders. Company CEO and co-founder Raymond Tesi says he expects to see those indicators improve, even in a short, three-month trial.
The best way to avoid Alzheimer’s is to prevent it from ever starting, which might require keeping brain inflammation to a minimum, particularly in later life. Preventative measures are already well known: eat healthy foods, sleep well, exercise regularly, minimize stress and avoid smoking and heavy drinking.
You can’t do anything about your genetics but living a healthy lifestyle will help control your inheritance, says Tanzi, who, along with Deepak Chopra, wrote a book on the topic, The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life. “It’s important to get that set point as high as possible.”
Beets have been shown to fight inflammation, lower blood pressure1,2 and aid detoxification. Studies also suggest they can help lower your risk for heart failure and stroke, and provide powerful benefits for your brain, largely due to their high nitrate content. Your body transforms nitrates into nitric oxide,3which enhances oxygenation and has beneficial impacts on your circulatory and immune systems.
Beets have been shown to fight inflammation, lower blood pressure1,2 and aid detoxification. Studies also suggest they can help lower your risk for heart failure and stroke, and provide powerful benefits for your brain, largely due to their high nitrate content. Your body transforms nitrates into nitric oxide,3which enhances oxygenation and has beneficial impacts on your circulatory and immune systems.
Nitric oxide4 is a soluble gas continually produced from the amino acid L-arginine inside your cells, where it supports endothelial function and protects your mitochondria. Nitric oxide also serves as a signaling or messenger molecule in every cell of your body. Many competitive athletes actually use beet juice for its nitric oxide-boosting benefits. Research shows raw beets may increase stamina during exercise by as much as 16 percent,5 courtesy of its nitric oxide boost.
Beets May Protect Against Development of Alzheimer’s Disease
Now, research presented at the 2018 American Chemical Society’s meeting6 in New Orleans claims beets may also be a powerful ally in the fight against Alzheimer’s disease,7,8 the most severe and lethal form of dementia. As reported by The Atlanta Journal-Constitution:9
“First they examined the possible cause of the condition. Although it’s unknown, doctors have previously pinpointed beta-amyloid, a sticky protein that can disrupt communication between the brain cells and neurons. When it clings to metals, such as copper or iron, the beta-amyloid peptides misfold and clump together, causing inflammation and oxidation.
Therefore, the scientists targeted foods known to improve oxygen flow and cognitive functions, including beets. The purple veggie has a compound called betanin that binds to metals, which could prevent the misfold of the peptides. To test their hypothesis, the scientists measured oxidation levels of the beta-amyloid when it was mixed with a betanin mixture, and they found that oxidation decreased by up to 90 percent exposed to the beet compound.
When clusters of beta-amyloid form, it triggers brain inflammation and oxidation of neurons, and researchers believe this oxidation is what causes irreparable damage to the brain cells. Oxidation is particularly severe when the beta-amyloid is bound to copper. In this experiment, oxidation was largely prevented when betanin from beets were added to the mix.
As noted by co-author Darrell Cole Cerrato,10 “We can’t say that betanin stops the misfolding [of amyloid beta] completely, but we can say that it reduces oxidation. Less oxidation could prevent misfolding to a certain degree, perhaps even to the point that it slows the aggregation of beta-amyloid peptides …”
While the researchers hope their finding will lead to the development of better Alzheimer’s drugs, there’s really no reason to wait for such developments, seeing how Alzheimer’s is primarily a disease predicated on diet and lifestyle. Indeed, in his presentation of the findings (see featured video), Cerrato notes that this is yet another piece of information people can use to improve their eating habits and lower their risk of disease:
“In an age where people are trying to look more at what they’re consuming and what they’re eating … this is another source of data people can use … [W]e’re trying to get you to do the same thing your mother was trying to get you to do when you were a kid, which is eat your vegetables … I think this will be a good step forward in looking at how we can preventatively treat Alzheimer’s.”
Beets Improve Neuroplasticity
Previous research11 has shown raw beet juice helps improve neuroplasticity, primarily by increasing blood flow and tissue oxygenation. Nitric oxide, in its capacity as a signaling molecule, also allows your brain cells to communicate with each other better. Importantly, the beets boosted oxygenation of the somatomotor cortex, a brain area that is often affected in the early stages of dementia.
Here, the beet juice was used in combination with exercise, which also improves blood flow and oxygenation on its own. The participants — middle-aged individuals diagnosed with high blood pressure — were given either beet juice or a placebo to drink three times a week, an hour before exercise, for six weeks.12,13,14 Exercise consisted of a 50-minute walk on a treadmill.
The results showed adding beet juice to your exercise regimen can be a simple yet powerful way to augment the benefits of exercise to your brain. Fermented beet juice powder might even be better as it still has the beneficial nutrients, and the carbs have been predigested by fermentation process. As noted by study co-author W. Jack Rejeski, a health and exercise science professor at Wake Forest University in North Carolina:15,16
“Nitric oxide … goes to the areas of the body which are hypoxic, or needing oxygen, and the brain is a heavy feeder of oxygen in your body … [W]hat we showed in this brief training study … was that, as compared to exercise alone, adding a beet root juice supplement to exercise resulted in brain connectivity that closely resembles what you see in younger adults.”
Two caveats are worthy of mention. First, avoid using harsh mouthwashes, as this will reduce the conversion of nitric oxide by killing off necessary microbes. Also avoid fluoridated water, as fluoride converts nitric oxide into harmful nitric acid.17 Fluoride also has other brain-harming influences, and has been shown to impair neurological functioning all on its own. It is, after all, classified as a neurotoxin.
Turmeric — Another Food Shown to Lower Alzheimer’s Risk
Another food that can bolster your neurological health is curcumin, an active ingredient found in the spice turmeric. Recent research shows turmeric supplementation helped improve memory and focus in seniors already suffering mild memory lapses, and reduced amyloid and tau deposits associated with Alzheimer’s.18
The double-blind, placebo-controlled study, published in the American Journal of Geriatric Psychiatry,19 included 40 adults between the ages of 50 and 90. None had a diagnosis of dementia at the time of their enrollment. Participants randomly received either 90 milligrams of curcumin twice a day for 18 months, or a placebo.
A standardized cognitive assessment was administered at the start of the study and at six-month intervals thereafter, and the level of curcumin in their blood was measured at the beginning and end of the study. Thirty of the participants also underwent positron emission tomography (PET) scans to assess their level of amyloid and tau deposits before and after treatment.
Those who received curcumin saw significant improvements in memory and concentration, while the control group experienced no improvement. Overall, the curcumin group improved their memory by 28 percent over the year-and-a-half-long treatment period. PET scans also confirmed the treatment group had significantly less amyloid and tau buildup in areas of the brain that control memory, compared to controls.
Curcumin has also been shown to increase levels of brain-derived neurotrophic factor (BDNF),20 and reduced levels of BDNF have been linked to Alzheimer’s disease. Yet another way curcumin may benefit your brain and lower your risk of dementia is by affecting pathways that help reverse insulin resistance, hyperlipidemia and other symptoms associated with metabolic syndrome and obesity.21
High-Sugar Diet Significantly Raises Your Risk of Dementia
Perhaps the most important dietary factor that impacts your Alzheimer’s risk is the amount of net carbs (total carbs minus fiber) you consume on a regular basis. A high-sugar diet triggers insulin resistance — currently thought to affect as many as 8 in 10 Americans22,23 — and there’s a very strong link between insulin resistance and Alzheimer’s.24
For example, a longitudinal study25 published in the journal Diabetologia in January 2018, which followed nearly 5,190 individuals for over a decade, found that the higher an individual’s blood sugar, the faster their rate of cognitive decline. Even mild elevation of blood sugar and mild insulin resistance are associated with an elevated risk for dementia.26,27 Diabetes and heart disease28 are also known to elevate your risk, and both are rooted in insulin resistance.
One of the most striking studies29 on carbohydrates and brain health revealed high-carb diets increase your risk of dementia by 89 percent, while high-fat diets lower it by 44 percent. According to the authors, “A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of mild cognitive impairment or dementia in elderly persons.”
Sugar Atrophies Your Hippocampus, Impairing Memory
Research30 published in 2013 showed that sugar and other carbohydrates can disrupt your brain function even if you’re not diabetic or have any signs of dementia. Here, short- and long-term glucose markers were evaluated in healthy, nondiabetic, nondemented seniors. Memory tests and brain imaging were also used to assess brain function and the actual structure of their hippocampus.
The findings revealed that the higher the two blood glucose measures, the smaller the hippocampus, the more compromised its structure, and the worse the individual’s memory was. According to the authors, the structural changes in the hippocampus alone can partially account for the statistical link we see between glucose and memory, as your hippocampus is involved with the formation, organization and storage of memories.
The results suggest glucose directly contributes to atrophy of the hippocampus, which means that even if you’re not insulin-resistant or diabetic, excess sugar may still be negatively affecting your memory. The authors suggest that “strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population.”
A similar study31 published in 2014 found that Type 2 diabetics lose more gray matter with age than expected, and this brain atrophy also helps explain why diabetics have a higher risk for dementia, and have earlier onset of dementia than nondiabetics.
As noted by Dr. Sam Gandy, director of the Center for Cognitive Health at Mount Sinai Hospital in New York City, these findings “suggest that chronic high levels of insulin and sugar may be directly toxic to brain cells” adding that “This would definitely be a potential cause of dementia.”32
Early Detection Could Save Trillions
Alzheimer’s is proving to be stubbornly resistant to conventional remedies. According to Bloomberg,33 more than 190 human drug trials have ended in failure, and despite a burgeoning epidemic, the best drugs on the market only ameliorate symptoms while adding other risks. This is why dietary prevention is so crucial. We simply cannot afford to ignore the importance of real food any longer. At present, the best conventional medicine can hope for is improved diagnosis.
According to a recent report by the Alzheimer’s Association,34 the U.S. currently spends $277 billion on dementia care each year,35,36 and that doesn’t include care by unpaid caregivers. About 70 percent of these costs are paid by the families through out-of-pocket expenses.
On average, the out-of-pocket expenses for caregivers of someone with dementia is $10,697 per year, and 40 percent of caregivers have an annual household income below $50,000. By 2050, we may be looking at a health care bill of $1.1 trillion per year to take care of our demented seniors. As reported by Bloomberg:
“… [S]ignificant cost savings can be achieved, according to the new report, by the simple act of early diagnosis. Currently, individuals are typically diagnosed in the dementia stage, rather than when they have developed only mild cognitive impairment. Identifying the disease early can allow it to be better managed, in part with existing drugs that treat its symptoms.
In doing so, the study postulates, America could save $7.9 trillion over the lifetimes of everyone alive right now … [M]anaged dementia is less expensive to treat because it reduces the chances of missing medication or incurring avoidable costs … It’s more costly to be diagnosed in the later stages because that’s likely to occur only after an expensive trip to the hospital.”
Early Detection Still Not as Good as Prevention
Considering 5.7 million Americans currently have Alzheimer’s and prevalence is projected to rise nearly 29 percent in the next seven years alone, it would behoove everyone to take prevention seriously, and begin taking proactive steps sooner rather than later. For while the financial costs may be steep, no price can be placed on the emotional and psychological costs associated with this tragic disease.
Early detection would surely be helpful, and strides are being made in the development of a blood test to detect Alzheimer’s.37 (In a recent trial,38 the test was 90 percent accurate in detecting the disease in a pool of 370 participants.)
One of the most comprehensive assessments of Alzheimer’s risk is Dr. Dale Bredesen’s ReCODE protocol, which evaluates 150 factors known to contribute to the disease. This protocol also identifies your disease subtype or combination of subtypes so that an effective treatment protocol can be devised.
You can learn more about this in “ReCODE: The Reversal of Cognitive Decline.” The full protocol is described in Bredesen’s book, “The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline.”39 However, if you’re diagnosed with early warning signs, that still means you’re on your way toward oblivion, and it didn’t need to get to that point in the first place.
As with cancer, early detection should not be confused with prevention, as diagnosing does not prevent you from having to figure out how to reverse the damage.
Your Diet Is a Key Consideration
Based on what we currently know, it seems foolish in the extreme to ignore dietary factors. As mentioned earlier, a key consideration is to reduce your net carb consumption and increase healthy fats. I believe the cyclical ketogenic diet I describe in my book “Fat for Fuel” can go a long way toward avoiding neurological degeneration by optimizing your mitochondrial function and biological regeneration.
Aside from eating real foods, paying careful attention to minimize net carbs, adding certain brain-boosting foods and supplements such as beets and curcumin can be helpful. Just don’t think you can continue eating junk food and just taking some beet juice and curcumin supplements.
With regard to beets, I recommend buying organic beets, or grow your own from heirloom beet seeds. While table beets are not genetically engineered (GE), they’re frequently grown in close proximity to sugar beets, most of which are GE, so there’s the potential for contamination via cross-pollination. While beets have the highest sugar content of all vegetables, most people can safely eat beet roots a few times a week. Beet root juice, however, should be consumed in moderation.
One way to circumvent the sugar issue is to ferment your beets. Not only does the fermentation process eliminate a majority of the sugars, it also makes the nutrients more bioavailable. Aside from pickled beets,40 other fermented beet products include beet-infused sauerkraut41 and kvass.42
There are also convenient fermented beet powders which I take and put in my breakfast smoothie nearly every day. By supplying beneficial bacteria, beet kvass can also have a very beneficial impact on diabetes and many other health problems, particularly those rooted in gut dysfunction.43
Because of its detoxifying properties, avoid drinking too much when first starting out. As a general recommendation, start out with 1 ounce per day, gradually increasing the amount to an 8-ounce glass per day. If you’re highly toxic, you may need to start out with as little as a tablespoon. For instructions and a simple recipe for beet kvass, see my previous article, “The Benefits of Fermented Beets.”
Alzheimer’s Prevention Strategies You Need to Know About
According to Dr. David Perlmutter, a neurologist and author of “Grain Brain” and “Brain Maker,” anything that promotes insulin resistance will ultimately also raise your risk of Alzheimer’s. To this I would add that any strategy that enhances your mitochondrial function will lower your risk. In 2014, Bredesen published a paper that demonstrates the power of lifestyle choices for the prevention and treatment of Alzheimer’s.
By leveraging 36 healthy lifestyle parameters, he was able to reverse Alzheimer’s in 9 out of 10 patients. This included the use of exercise, ketogenic diet, optimizing vitamin D and other hormones, increasing sleep, meditation, detoxification and eliminating gluten, and processed food. You can download Bredesen’s full-text case paper online, which details the full program.44 Following are some of the lifestyle strategies I believe to be the most helpful and important:
Eat real food, ideally organic Avoid processed foods of all kinds, as they contain a number of ingredients harmful to your brain, including refined sugar, processed fructose, grains (particularly gluten), vegetable oils, genetically engineered ingredients and pesticides. Ideally, keep your added sugar to a minimum and your total fructose below 25 grams per day, or as low as 15 grams per day if you already have insulin/leptin resistance or any related disorders. Opting for organic produce will help you avoid synthetic pesticides and herbicides. Most will also benefit from a gluten-free diet, as gluten makes your gut more permeable, which allows proteins to get into your bloodstream where they sensitize your immune system and promote inflammation and autoimmunity, both of which play a role in the development of Alzheimer’s.
Replace refined carbs with healthy fats Diet is paramount, and the beauty of following my optimized nutrition plan is that it helps prevent and treat virtually all chronic degenerative diseases, including Alzheimer’s. It’s important to realize that your brain actually does not need carbs and sugars; healthy fats such as saturated animal fats and animal-based omega-3 are far more critical for optimal brain function. A cyclical ketogenic diet has the double advantage of both improving your insulin sensitivity and lowering your Alzheimer’s risk. As noted by Perlmutter, lifestyle strategies such as a ketogenic diet can even offset the risk associated with genetic predisposition. When your body burns fat as its primary fuel, ketones are created, which not only burn very efficiently and are a superior fuel for your brain, but also generate fewer reactive oxygen species and less free radical damage. A ketone called beta hydroxybutyrate is also a major epigenetic player, stimulating beneficial changes in DNA expression, thereby reducing inflammation and increasing detoxification and antioxidant production. I explain the ins and outs of implementing this kind of diet, and its many health benefits, in my book, “Fat for Fuel.” In it, I also explain why cycling through stages of feast and famine, opposed to continuously remaining in nutritional ketosis, is so important. Pay close attention to the kinds of fats you eat — avoid all trans fats or hydrogenated fats that have been modified in such a way to extend their longevity on the grocery store shelf. This includes margarine, vegetable oils and various butter-like spreads. Healthy fats to add to your diet include avocados, butter, organic pastured egg yolks, coconuts and coconut oil, grass fed meats, and raw nuts such as pecans and macadamia. MCT oil is also a great source of ketone bodies.
Keep your fasting insulin levels below 3 Lowering your insulin will also help lower leptin levels, which is another factor for Alzheimer’s. If your insulin is high, you’re likely consuming too much sugar and need to cut back.
Optimize your omega-3 levelAlso make sure you’re getting enough animal-based omega-3 fats. High intake of the omega-3 fats EPA and DHA help by preventing cell damage caused by Alzheimer’s disease, thereby slowing down its progression and lowering your risk of developing the disorder. Ideally, get an omega-3 index test done once a year to make sure you’re in a healthy range. Your omega-3 index should be above 8 percent and your omega 6-to-3 ratio between 0.5 and 3.0.
Optimize your gut floraTo do this, avoid processed foods, antibiotics and antibacterial products, fluoridated and chlorinated water, and be sure to eat traditionally fermented and cultured foods, along with a high-quality probiotic if needed. Dr. Steven Gundry does an excellent job of expanding on this in his book “The Plant Paradox.”
Intermittently fastIntermittent fasting is a powerful tool to jumpstart your body into remembering how to burn fat and repair the insulin/leptin resistance that is a primary contributing factor for Alzheimer’s. Once you have worked your way up to where you’ve been doing 20-hour daily intermittent fasting for a month, are metabolically flexible and can burn fat as your primary fuel, you can progress to the far more powerful five-day water fasts.
Move regularly and consistently throughout the day It’s been suggested that exercise can trigger a change in the way the amyloid precursor protein is metabolized,45 thus, slowing down the onset and progression of Alzheimer’s. Exercise also increases levels of the protein PGC-1 alpha. Research has shown that people with Alzheimer’s have less PGC-1 alpha in their brains and cells that contain more of the protein produce less of the toxic amyloid protein associated with Alzheimer’s.
Optimize your magnesium levels Preliminary research strongly suggests a decrease in Alzheimer symptoms with increased levels of magnesium in the brain. Keep in mind that the only magnesium supplement that appears to be able to cross the blood-brain barrier is magnesium threonate.
Optimize your vitamin D, ideally through sensible sun exposure Sufficient vitamin D is imperative for proper functioning of your immune system to combat inflammation associated with Alzheimer’s and, indeed, research shows people living in northern latitudes have higher rates of death from dementia and Alzheimer’s than those living in sunnier areas, suggesting vitamin D and/or sun exposure are important factors.46If you are unable to get sufficient amounts of sun exposure, take daily supplemental vitamin D3 to reach and maintain a blood level of 60 to 80 ng/ml. That said, it’s important to recognize that sun exposure is important for reasons unrelated to vitamin D. Your brain responds to the near-infrared light in sunlight in a process called photobiomodulation. Research shows near-infrared stimulation of the brain boosts cognition and reduces symptoms of Alzheimer’s, including more advanced stages of the disease.Delivering near-infrared light to the compromised mitochondria synthesizes gene transcription factors that trigger cellular repair, and your brain is one of the most mitochondrial-dense organs in your body.
Avoid and eliminate mercury from your body Dental amalgam fillings are one of the major sources of heavy metal toxicity, however you should be healthy prior to having them removed. Once you have adjusted to following the diet described in my optimized nutrition plan, you can follow the mercury detox protocol and then find a biological dentist to have your amalgams removed.
Avoid and eliminate aluminum from your body Common sources of aluminum include antiperspirants, nonstick cookware and vaccine adjuvants. For tips on how to detox aluminum, please see my article, “First Case Study to Show Direct Link between Alzheimer’s and Aluminum Toxicity.” There is some suggestion that certain mineral waters high in silicic acid may help your body eliminate aluminum.
Avoid flu vaccinations Most flu vaccines contain both mercury and aluminum.
Avoid statins and anticholinergic drugs Drugs that block acetylcholine, a nervous system neurotransmitter, have been shown to increase your risk of dementia. These drugs include certain nighttime pain relievers, antihistamines, sleep aids, certain antidepressants, medications to control incontinence and certain narcotic pain relievers. Statin drugs are particularly problematic because they suppress the synthesis of cholesterol, deplete your brain of coenzyme Q10, vitamin K2 and neurotransmitter precursors, and prevent adequate delivery of essential fatty acids and fat-soluble antioxidants to your brain by inhibiting the production of the indispensable carrier biomolecule known as low-density lipoprotein.
Limit your exposure to dangerous EMFs (cellphones, Wi-Fi routers and modems) Radiation from cellphones and other wireless technologies trigger excessive production of peroxynitrites,47 a highly damaging reactive nitrogen species. Increased peroxynitrites from cellphone exposure will damage your mitochondria,48,49 and your brain is the most mitochondrial-dense organ in your body. Increased peroxynitrite generation has also been associated with increased levels of systemic inflammation by triggering cytokine storms and autonomic hormonal dysfunction.
Optimize your sleep Sleep is necessary for maintaining metabolic homeostasis in your brain. Without sufficient sleep, neuron degeneration sets in, and catching up on sleep during weekends will not prevent this damage.50,51,52 Sleep deprivation causes disruption of certain synaptic connections that can impair your brain’s ability for learning, memory formation and other cognitive functions. Poor sleep also accelerates the onset of Alzheimer’s disease.53Most adults need seven to nine hours of uninterrupted sleep each night. Deep sleep is the most important, as this is when your brain’s glymphatic system performs its cleanout functions, eliminating toxic waste from your brain, including amyloid beta.
Challenge your mind daily Mental stimulation, especially learning something new, such as learning to play an instrument or a new language, is associated with a decreased risk of dementia and Alzheimer’s. Researchers suspect that mental challenge helps to build up your brain, making it less susceptible to the lesions associated with Alzheimer’s disease.
The two ‘super-organisms’ seem to follow the same rules.
The human brain follows certain laws, which govern how the complex organ reacts to stimuli and makes decisions. In a new study, scientists argue that super-organisms like honeybees follow the same laws: Like neurons in the brain, they argue, the different bees in a colony coordinate their responses to external stimuli according to strict rules. This discovery suggests, for the first time, that psychological and physical laws don’t just operate in human brains but drive other natural behaviors as well.
In the study, released Tuesday in Scientific Reports, researchers from the University of Sheffield and the Italian National Research Council observe bees to better understand the basic principles that guide these laws. If bees follow the same laws as neurons, then observing them can lead to a better understanding of the human brain. Studying bee colonies, they figure, is simpler than watching the neurons of a brain while a human makes a decision.
“This study is exciting because it suggests that honeybee colonies adhere to the same laws as the brain when making collective decisions,” co-author Andreagiovannia Reina, Ph.D. explained in a statement released Tuesday. “This study also supports the view of bee colonies as being similar to complete organisms or better still, super-organisms, composed of a large number of fully developed and autonomous individuals that interact with each other to bring forth a collective response.”
Bees operate as a super-organism.
Most biologists refer to honeybees as super-organisms, wherein the individuals comprising a hive are comparable to the cells that make up a single organism. Working together through structured, cooperative behavior bolsters the hive’s chance for survival. The ability to make decisions collectively has previously been compared to the way a brain’s different parts are involved in cognitive deliberation, but here, the scientists take the analysis a step further by observing how bees make the difficult decision of choosing a nest location for the entire group.
In the spring, colonies of European bees go through a mix-up: Part of the swarm leaves to find the best possible nesting location, while the other half stays behind to protect the queen. After exploring, scout bees return to the hive to recruit other scouts to check out the site, delivering “stop signals.” When the honeybees reach a collective agreement for the same option, the colony moves.
Hives are chosen via collective decision making.
This process became the basis of the researchers’ theoretical model, which led the researchers to determine that the bee colony acts as a single super-organism that then coordinates a response to an external stimulus. They conclude, in the statement accompanying the paper, that “the way in which bees ‘speak’ with each other and make decisions is comparable to the way the many individual neurons in the human brain interact with each other.”
Just as individual neurons in the brain don’t obey psychophysical laws themselves but do so as part of the whole brain, single bees sometimes fire off different signals than the other bees. But regardless, the super-organism still obeys the rules — just like the brain.
And, just like bees, the human brain is known to follow certain rules. Pieron’s Law, for example, states that the brain makes decisions more quickly when the options to choose from are all of high quality. Hick’s Law, meanwhile, shows that the brain makes decisions more slowly when the number of options increases; with their model, the scientists determined that decision-making among bees follows similar guidelines. The colony chooses the location of their new hive more quickly when it has high-quality nest-site options and does so more slowly when the site options are limited.
Then, there’s Weber’s Law, which states that the brain selects the best option when there is a “minimum difference between the qualities of the options.” Like the brain, bee colonies were shown to do the same.
“With this view in mind, parallels between bees in a colony and neurons n a brain can be traced,” says Reina, “helping us to understand and identify the general mechanisms underlying psychophysics laws, which may ultimately lead to a better understanding of the human brain.”
How does memory work? The further we seem to dive in, the more questions we stumble upon about how the function of memory first evolved. Scientists made a key breakthrough with the identification of the Arc protein in 1995, observing how its role in the plastic changes in neurons was critical to memory consolidation.
This protein is already a big deal, but the Arc picture just got a lot more interesting. In a study published Thursday in the journal Cell, a team of researchers at the University of Utah, the University of Copenhagen in Denmark, and MRC Laboratory of Molecular Biology in Cambridge, UK, argue that Arc took its place in the brain as a result of a random chance encounter millions of years ago. Similar to how scientists say the mitochondria in our cells originated as bacteria that our ancient ancestors’ cells absorbed, the Arc protein seems to have started as a virus.
Much as a virus infects host cells, Arc can deliver genetic material to brain cells.
The researchers knew they were onto something when they captured an image of Arc that looked an awful lot like a viral capsid, the isohedral protein coat that encapsulates a virus’s genetic material for delivery to host cells during infection.
“At the time, we didn’t know much about the molecular function or evolutionary history of Arc,” says study coauthor Jason Shepherd, an assistant professor of neurobiology, anatomy, biochemistry, and ophthalmology at the University of Utah, in a statement. Shepherd has studied Arc for 15 years. “I had almost lost interest in the protein, to be honest. After seeing the capsids, we knew we were onto something interesting.”
The main issue that challenges neuroscientists’ understanding of memory is that proteins don’t last very long in the brain, even though memories last nearly a lifetime. So for memories to remain, there must be plastic changes, meaning that neuron structures actually have to change as a result of memory consolidation.
This is where Arc comes into play. Previous research on rats illustrated how Arc disrupts memory consolidation, suggesting that Arc is vital in neuronal plasticity.
But scientists never thought they would stumble on evidence that pointed to a viral origin for Arc, as these new findings suggest.
The research team needed to verify this theory, so they tested whether Arc actually acts like a virus. It turns out the Arc capsid encapsulated its own RNA. When they put the Arc capsids into a mouse brain cell culture, the capsids transferred their RNA to the mouse brain cells — just like viral infection does.
“We went into this line of research knowing that Arc was special in many ways, but when we discovered that Arc was able to mediate cell-to-cell transport of RNA, we were floored,” says the study’s lead author, postdoctoral fellow Elissa Pastuzyn, Ph.D., in a statement. “No other non-viral protein that we know of acts in this way.”
The researchers suspect this virus-mammal collaboration happened sometime between 350 and 400 million years ago when a retrotransposon — the ancestor of modern retroviruses — got its DNA into a four-legged creature. They also suspect that this happened more than once. If they’re right, this research complicates the picture of the evolution of life as we know it. Not only did many mutations happen by random chance to make us what we are today, but we actually borrowed biology from other cells and organisms to get here. A little bit of their history lives on in us today.
Abstract: The neuronal gene Arc is essential for long-lasting information storage in mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. However, little is known about Arc’s molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties of retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.
The numbers are mind-boggling, but the way each individual nerve cell contributes to the brain’s functions is still an area of contention. A new study has overturned a hundred-year-old assumption on what exactly makes a neuron ‘fire’, posing new mechanisms behind certain neurological disorders.
A team of physicists from Bar-Ilan University in Israel conducted experiments on rat neurons grown in a culture to determine exactly how a neuron responds to the signals it receives from other cells.
To understand why this is important, we need to go back to 1907 when a French neuroscientist named Louis Lapicque proposed a model to describe how the voltage of a nerve cell’s membrane increases as a current is applied.
Once reaching a certain threshold, the neuron reacts with a spike of activity, after which the membrane’s voltage resets.
What this means is a neuron won’t send a message unless it collects a strong enough signal.
Lapique’s equations weren’t the last word on the matter, not by far. But the basic principle of his integrate-and-fire model has remained relatively unchallenged in subsequent descriptions, today forming the foundation of most neuronal computational schemes.
Image credit: NICHD/Flickr
According to the researchers, the lengthy history of the idea has meant few have bothered to question whether it’s accurate.
“We reached this conclusion using a new experimental setup, but in principle these results could have been discovered using technology that has existed since the 1980s,” says lead researcher Ido Kanter.
“The belief that has been rooted in the scientific world for 100 years resulted in this delay of several decades.”
The experiments approached the question from two angles – one exploring the nature of the activity spike based on exactly where the current was applied to a neuron, the other looking at the effect multiple inputs had on a nerve’s firing.
Their results suggest the direction of a received signal can make all the difference in how a neuron responds.
A weak signal from the left arriving with a weak signal from the right won’t combine to build a voltage that kicks off a spike of activity. But a single strong signal from a particular direction can result in a message.
This potentially new way of describing what’s known as spatial summation could lead to a novel method of categorising neurons, one that sorts them based on how they compute incoming signals or how fine their resolution is, based on a particular direction.
Better yet, it could even lead to discoveries that explain certain neurological disorders.
It’s important not to throw out a century of wisdom on the topic on the back of a single study. The researchers also admit they’ve only looked at a type of nerve cell called pyramidal neurons, leaving plenty of room for future experiments.
But fine-tuning our understanding of how individual units combine to produce complex behaviours could spread into other areas of research. With neural networks inspiring future computational technology, identifying any new talents in brain cells could have some rather interesting applications.
A new technology shows real-time communication among neurons that promises to reveal brain activity in unprecedented detail.
In a mouse brain, cell-based detectors called CNiFERs change their fluorescence when neurons release dopamine.
When a single neuron fires, it is an isolated chemical blip. When many fire together, they form a thought. How the brain bridges the gap between these two tiers of neural activity remains a great mystery, but a new kind of technology is edging us closer to solving it.
The glowing splash of cyan in the photo above comes from a type of biosensor that can detect the release of very small amounts of neurotransmitters, the signaling molecules that brain cells use to communicate. These sensors, called CNiFERs (pronounced “sniffers”), for cell-based neurotransmitter fluorescent engineered reporters, are enabling scientists to examine the brain in action and up close.
This newfound ability, developed as part of the White House BRAIN Initiative, could further our understanding of how brain function arises from the complex interplay of individual neurons, including how complex behaviors like addiction develop. Neuroscientist Paul Slesinger at Icahn School of Medicine at Mount Sinai, one of the senior researchers who spearheaded this research, presented the sensors Monday at the American Chemical Society’s 252nd National Meeting & Exposition.
Current technologies have proved either too broad or too specific to track how tiny amounts of neurotransmitters in and around many cells might contribute to the transmission of a thought. Scientists have used functional magnetic resonance imaging to look at blood flow as a surrogate for brain activity over fairly long periods of time or have employed tracers to follow the release of a particular neurotransmitter from a small set of neurons for a few seconds. But CNiFERs make for a happy medium; they allow researchers to monitor multiple neurotransmitters in many cells over significant periods of time.
When a CNiFER comes in contact with the neurotransmitter it is designed to detect, it fluoresces. Using a tiny sensor implanted in the brain, scientists can then measure how much light the CNiFER emits, and from that infer the amount of neurotransmitter present. Because they comprise several interlocking parts, CNiFERs are highly versatile, forming a “plug-and-play system,” Slesinger says. Different sections of the sensor can be swapped out to detect individual neurotransmitters. Prior technology had trouble distinguishing between similar molecules, such as dopamine and norepinephrine, but CNiFERs do not.
The sensors are being tested in animals to examine particular brain processes. Slesinger and his colleagues have used CNiFERs to look more closely at a classic psychological phenomenon: Pavlovian conditioning. Just as Pavlov trained his dog to salivate at the sound of a dinner bell, Slesinger and his team trained mice to associate an audio cue with a food reward. At the beginning of the experiment, the mice experienced a release of dopamine and norepinephrine when they received a sugar cube. As the animals became conditioned to associate the audio cue with the sugar, however, the neurotransmitter release occurred earlier, eventually coinciding with the audio cue rather than the actual reward.
Mouse studies might be a far cry from the kind of human impact that neuroscience ultimately strives toward—better treatments for Parkinson’s patients or concussion sufferers, for example—but this is where it all begins. Slesinger is especially interested in using CNiFERs to study addiction. A more nuanced understanding of how addiction develops in mouse brains could help identify novel targets to combat addiction in people.
Neurons in the brain interact by sending each other neurotransmitters, of which gamma-aminobutyric acid (GABA) is the most common inhibitory one. GABA is important to restrain neural activity, preventing neurons from getting too trigger-happy and from firing too much or responding to irrelevant stimuli.
Researchers led by Dr Tobias Bast in the School of Psychology at The University of Nottingham have found that faulty inhibitory neurotransmission and abnormally increased activity in the hippocampus impairs our memory and attention.
Their latest research, published in the academic journal Cerebral Cortex, has implications for understanding cognitive deficits in a variety of brain disorders, including schizophrenia, age-related cognitive decline and Alzheimer’s, and for the treatment of cognitive deficits.
The hippocampus plays a major role in our everyday memory of events and of where and when they happen—for example remembering where we parked our car before going shopping.
This research has shown that a lack of restraint in the neural firing within the hippocampus disrupts hippocampus-dependent memory; in addition, such aberrant neuron firing within the hippocampus also disrupted attention—a cognitive function that does not normally require the hippocampus.
Increased activity can be more detrimental than reduced activity
Dr Bast, said: “Our research carried out in rats highlights the importance of GABAergic inhibition within the hippocampus for memory performance and for attention. The finding that faulty inhibition disrupts memory suggests that memory depends on well-balanced neural activity within the hippocampus, with both too much and too little causing impairments. This is an important finding because traditionally, memory impairments have mainly been associated with reduced activity or lesions of the hippocampus.
“Our second important finding is that faulty inhibition leading to increased neural activity within the hippocampus disrupts attention, a cognitive function that does not normally require the hippocampus, but depends on the prefrontal cortex. This probably reflects that there are very strong neuronal connections between hippocampus and prefrontal cortex. Our finding suggests that aberrant hippocampal activity has a knock-on effect on the prefrontal cortex, thereby disrupting attention.”
“Overall, our new findings show that increased activity of a brain region, due to faulty inhibitory neurotransmission, can be more detrimental to cognitive function than reduced activity or a lesion. Increased activity within a brain region can disrupt not only the function of the region itself—in this case hippocampus-dependent memory—but also the function of other regions to which it is connected—in this case prefrontal cortex-dependent attention.”
Adding to existing research findings
Dr Bast’s research is motivated by recent clinical findings that patients in early stages of schizophrenia, age-related cognitive decline and Alzheimer’s show faulty inhibition and increased activity within the hippocampus. The new study, where inhibition in the hippocampus of rats was disrupted before the animals took part in tests of attention and memory, revealed that such faulty inhibition and aberrant activity within the hippocampus causes the type of memory and attentional impairments seen in patients.
This research adds to the team’s recent findings, where they found that attention was disrupted by faulty inhibition and increased activity within the prefrontal cortex, a brain region important for attention.
Dr Bast, said: “Overall, these findings highlight that higher brain functions, such as attention and memory, depend on well-balanced neural activity within the underlying brain regions.”
Potential target for new treatments
This research has important implications for treating cognitive impairments.
The findings show that simply ‘boosting’ the activity of the key memory and attention centres in the brain (the hippocampus and prefrontal cortex), which has been a long-standing strategy for cognitive enhancement, will not necessarily improve memory and attention, but can actually impair these functions. What’s important is to re-balance activity within these regions.
Dr Bast, said: “One emerging idea is that early stages of cognitive disorders, such as schizophrenia and age-related cognitive decline and Alzheimer’s, are characterised by faulty inhibition and too much activity; this excess neural activity leads then to neuronal damage and the reduced brain activity characterizing later stages of these disorders. So, rebalancing aberrant activity early on may not only restore attention and memory, but also prevent further decline.
“We have new studies on the way where we aim to identify medicines that might be able to re-balance neural activity within hippocampus and prefrontal cortex and to restore memory and attention.”
Thick section of mammalian brain, gold stained for astrocytes.
ALS research shows that aging astrocytes lose the ability to protect motor neurons, but replacing old cells with younger ones engineered to restore an important protein may improve neuron survival
Amyotrophic lateral sclerosis (ALS), attacks motor neurons in the brain, brainstem and spinal cord, leading to progressive weakness and eventual paralysis of muscles throughout the body. Patients typically survive only three to five years after diagnosis.
Now, with publication of a study by investigators at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, ALS researchers know the effects of the attack are worsened, at least in part, by the aging and failure of support cells called astrocytes, which normally provide nutrients, housekeeping, structure and other forms of assistance for neurons.
Earlier studies suggested the possible involvement of these support cells in ALS development and progression, but the new research is believed to be the first to directly measure the effects of aging on the ability of astrocytes to sustain motor neurons. Results are published online inNeurobiology of Aging.
The Cedars-Sinai researchers first tried to repeat previous studies showing that astrocytes from laboratory animals with an ALS mutation failed to support normal motor neurons. They were surprised to find that very young ALS astrocytes were supportive, but ALS astrocytes from older animals were not. More surprisingly, it wasn’t just diseased astrocytes that were affected by age. The scientists discovered — and reported for the first time — that even normal aging of astrocytes reduces their ability to support motor neurons.
“Aging astrocytes lose their ability to support motor neurons in general, and they clearly fail to help those attacked by ALS,” said Clive Svendsen, PhD, professor and director of the Board of Governors Regenerative Medicine Institute, the article’s senior author.
He said old astrocytes and ALS-affected astrocytes have lower death rates in the petri dish than younger ones — they seem to hang around longer and accumulate. But while older astrocytes and those with the ALS mutation live longer, they appear to have significant damage to their DNA. Instead of being cleared away for replacement by new, healthy cells, the old, defective cells become useless clutter, producing chemicals that cause harmful inflammation. The process is accelerated in ALS astrocytes.
“Our findings have implications for scientists studying neurodegenerative diseases like ALS and Alzheimer’s and the aging process in general. In younger animals modeling ALS and in older ‘normal’ animals, the accumulations of defective astrocytes in the nervous system look similar,” said Melanie Das, PhD, a student in the Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine, the article’s first author.
After establishing the effects of aging on astrocytes, the researchers took another step — evaluating the potential therapeutic effects of a specially engineered protein.
“We found that by culturing aging astrocytes and those harboring the ALS mutation with a neuron-protective protein called GDNF, we could increase motor neuron survival. We already knew that GDNF was protective directly on motor neurons, but we believe this is the first time that the delivery of GDNF has been shown to have a direct beneficial effect on astrocytes, perhaps resetting their aging clock, which ultimately benefits neurons,” Svendsen said.
Svendsen and scientists in his laboratory have studied GDNF extensively, devising experimental methods to restore beneficial levels in the brain and spinal cord — where the disease originates — and in muscles, at the point where nerve fibers connect with muscle fibers to stimulate muscle action. Several large GDNF-related research projects taking shape at Cedars-Sinai are funded by the California Institute for Regenerative Medicine.
“Our major CIRM-funded programs, aimed at engineering young stem cell-derived astrocytes to secrete GDNF, then transplanting those cells back into patients, take on even greater importance, given this aging phenomenon,” said Svendsen, the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.
Birds are remarkably intelligent, although their brains are small. Corvids and some parrots are capable of cognitive feats comparable to those of great apes. How do birds achieve impressive cognitive prowess with walnut-sized brains? We investigated the cellular composition of the brains of 28 avian species, uncovering a straightforward solution to the puzzle: brains of songbirds and parrots contain very large numbers of neurons, at neuronal densities considerably exceeding those found in mammals. Because these “extra” neurons are predominantly located in the forebrain, large parrots and corvids have the same or greater forebrain neuron counts as monkeys with much larger brains. Avian brains thus have the potential to provide much higher “cognitive power” per unit mass than do mammalian brains.
Abstract
Some birds achieve primate-like levels of cognition, even though their brains tend to be much smaller in absolute size. This poses a fundamental problem in comparative and computational neuroscience, because small brains are expected to have a lower information-processing capacity. Using the isotropic fractionator to determine numbers of neurons in specific brain regions, here we show that the brains of parrots and songbirds contain on average twice as many neurons as primate brains of the same mass, indicating that avian brains have higher neuron packing densities than mammalian brains. Additionally, corvids and parrots have much higher proportions of brain neurons located in the pallial telencephalon compared with primates or other mammals and birds. Thus, large-brained parrots and corvids have forebrain neuron counts equal to or greater than primates with much larger brains. We suggest that the large numbers of neurons concentrated in high densities in the telencephalon substantially contribute to the neural basis of avian intelligence.
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