CAN ALZHEIMER'S BE ERASED?

New research in mice has shown for the first time that it's possible to stop the formation of amyloid plaques--one of the key pathological features of Alzheimer's disease--and for the brain to clear them away entirely. This line of research has the potential to lead to medications that can slow, stop, or perhaps even reverse the ravages of this dread, mind-destroying disease.

 

 Comparison of a healthy brain and a brain with severe Alzheimer's disease

Credit: Wikimedia

As many people know through personal experience with friends or family members, Alzheimer's is an implacably progressive neurodegenerative disease that  robs individuals of their memory, cognitive functions, ability to care for themselves, personalities and, eventually, their lives. It's currently the sixth leading cause of death in the U.S. and, strikingly, ". . . is the only disease in the 10 leading causes of deaths in the United States that cannot be cured, prevented or slowed."

A new study, however, opens up the possibility that Alzheimer's may in fact one day be slowed or prevented, if not cured. Working with mice genetically modified to develop Alzheimer's disease, neuroscientist Riqiang Yan* and his colleagues at the Cleveland Clinic-Lerner Research Institute in Cleveland, Ohio, found that gradually reducing an enzyme called BACE1 blocked the development of amyloid plaques, which are a central part of Alzheimer's pathology.

Although their study was complex and highly technical, the logic behind it is clear. BACE1 is one of two enzymes that snip amyloid precursor protein, or APP, into the shorter pieces that glom together into the plaques that are thought to disrupt and eventually kill neurons. Since BACE1 has important biological functions, removing it early in life or completely creates serious neuro-developmental problems. Still, the researchers reasoned, reducing it gradually in adult mice might slow or stop Alzheimer's without causing unacceptable side effects. That's exactly what they found.

"In our study," says Yan, " we showed that if we delete BACE1 in the adult mice, even after plaque formed, with sequential and increased deletion of BACE1 the plaque was removed. That indicates that if we can get to a patient early enough, it will be beneficial in removing amyloid plaque."

Yan was not surprised to see that lowered levels of BACE1 slowed or stopped the formation of new plaques. He was both surprised and excited to find already existing plaques cleared away--the first time that this has been seen. "To our knowledge," he says, "this is the first observation of such a dramatic reversal of amyloid deposition in any study of Alzheimer’s disease mouse models. We didn't expect the pre-existing plaque would be removed. That was the very interesting part, and warrants additional study to find out why."

While completely blocking BACE1 causes developmental and cognitive problems, a gradual lowering in adult mice appeared appeared safer. Those mice performed better on learning and memory tasks than untreated Alzheimer's prone mice.  However, they still showed some abnormalities in synaptic signalling. Despite this problem, Yan thinks that compounds can be developed that, when applied at the right time and at the right dose, will slow or stop the development of plaques, allow the brain to clear away existing ones, and so keep Alzheimer's at bay.

Prevention is more powerful than treatment

Yan compares this to the enormously successful use of statins to control cholesterol levels enough to block the development of atherosclerosis and heart disease, even though cholesterol has vital functions in the body. "The critical thing is will this lead to some safe drugs?" he asks. "We need to find something very safe like a vitamin that people can take every day without any concerns. Another similarity is to the statins, taking statins to prevent cholesterol from building up. The idea is that prevention is even more powerful that treatment." 

The next step for Yan and colleagues is to track the effects of reduced BACE1 on the mouse brain in more detail and on older mice. "Human patients are typically older than in the mouse model," he explains. "In the mouse model we started to delete [BACE1] at 4 months, which is like 20 years old for people. We now want to delete it in older mice. We need a new mouse model for this later stage."

Robert Vassar is a professor of neurology at Northwestern University, in Illinois, and a pioneer in the study of the role of BACE1 in Alzheimer's disease. He's very supportive of Yan's new findings, and, like Yan, thinks they hold significant promise for Alzheimer's prevention. Vassar too likes the analogy with statins and cardiovascular disease. "You can't turn off the tap of cholesterol, but you can turn it down enough to not accumulate the plaques in the heart that cause heart disease," he says. "It's saved the lives of many people. The BACE1 inhibitors can do the same, if we find the right dose and the right stage of the disease--how much to inhibit and when to treat." 

Vassar and Yan are both aware that years of further research with animals and humans are needed to turn these promising findings into a safe and effective preventative treatment for people. They foresee a long road, but one that urgently needs to be followed. "We have to bold about this disease," says Vassar.  "We're headed for an epidemic of this with the baby boomers, so we've got to do something."

As a baby boomer myself, I couldn't agree more!

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You can access Yan and his colleagues' full research paper here.

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*Professor Yan is currently Chair of the Department of Neuroscience and William Beecher Scoville Professor in Neuroscience at the University of Connecticut, in Farmington, Connecticut.

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TK






TK

AN INFECTIOUS IDEA -- A VIRUS-LIKE PROTEIN MAY BE CRUCIAL TO LEARNING AND MEMORY

We've all heard the phrase, "an infectious idea." It turns out that this may not just be a metaphor--new research has revealed that a virus-like protein in all of our brains may be vital for learning and memory.

"If it looks like a duck and quacks like a duck," the saying goes, "it probably is a duck." So, no matter how surprising it is, finding a crucial protein in the brain that looks like a virus and acts like a virus raises the intriguing possibility that our ability to learn and remember may stem from a chance infection of some ancestral four-legged creature by a retrovirus 350 to 400 million years ago.

The protein in question is called Arc. It's found in animals as different as flies, mice and humans. It's been known for some time that Arc is important for learning and memory. Mice lacking Arc forget what they've learned within 24 hours, and lack the kind of brain plasticity that lets young animals, most notably human children, soak up new information quickly and easily. Arc continues to be important for learning and memory throughout life, and impaired Arc functioning is associated with autism, amnesia and Alzheimer's disease.

Arc (long purple proteins inside the perimeter of the vesicle) can encapsulate and deliver its own genetic material to brain cells (light green branching blobs) in a manner similar to the way in which viruses infect host cells.  

Credit: Jacobo Lopez, Yi-Chu Su, Hugo Vaca

Jason Shepherd, a neuroscientist at the University of Utah, and his colleagues first suspected that something was different about Arc when they found that the protein self-assembles into structures called capsids that look like a lunar lander or the HIV retrovirus. Intrigued, they found that not only can the Arc capsid jump from cell to cell like a virus, it also transfers its own genetic material in the form of messenger RNA into the new cell.

Learning takes place when interconnected brain cells are activated at the same time. Intriguingly, the researchers found that when neurons "infected" by Arc are activated, they release newly minted Arc capsids. This suggests that the transfer of this virus-lilke protein from cell to cell may be a previously unknown and unsuspected mechanism for learning and memory.

Neuron expressing Arc and transferring it to other neurons

Credit: Elissa Pastuzyn 

“We went into this line of research knowing that Arc was special in many ways," says the study’s lead author, postdoctoral fellow Elissa Pastuzyn. "But when we discovered that Arc was able to mediate cell-to-cell transport of RNA, we were floored. No other non-viral protein that we know of acts in this way.”

Geneticists have been able to trace back the history of the Arc proteins found in all mammals. Sometime between 350 and 400 million years ago, a primitive four-limbed creature, or tetrapod, was infected by a retrovirus that left some of its genetic material in the animal's DNA. That chance addition to the mammalian genetic code has apparently proven extremely useful, perhaps laying the groundwork for the success of our mammalian ancestors, and even for our remarkable capacity for learning and remembering.

REA

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You can read more about this research at this URL.

The scientific article describing this research can be found in Cell, January 11, 2018.

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YOU KNOW THOSE BRAIN-TRAINING EXERCISES--THEY MAY ACTUALLY MAKE A DIFFERENCE

If you type "brain training exercises" or "brain training games" into a search engine, you'll get millions of hits. Companies offering games and exercise promising to ward off failing memory, loss of concentration and other signs of cognitive decline have become big business. These exercises have also become controversial, with some studies and experts highly critical of their usefulness.

Brain-training research, Brain and Mind Centre/Credit: University of Sydney

A new study published today in the American Journal of Psychiatry can shed some light on this issue. Researchers at the Brain and Mind Centre at the University of Sydney, in Australia, reviewed more than twenty years worth of research on the effects of computerized cognitive training (CCT). They selected only randomized clinical studies, and used the statistical technique of meta-analysis to combine the results. 

Their findings are surprisingly clear--for people with mild cognitive impairment, structured brain training can boost general thinking skills, attention, working or short-term memory, verbal long-term memory, learning and mood. 

Mild cognitive impairment, or MCI, represents a kind of middle ground between the kinds of memory and other cognitive problems that occur with normal ageing and the more severe changes seen in Alzheimer's disease and other full-blown dementias. Typically about 10 percent of people diagnosed with MCI develop Alzheimer's or another form of dementia within a year.

In general, the kinds of computerized games and challenges studied did not help after people had already been diagnosed with dementia. Intriguingly, however, three studies that used more immersive technology such as Nintendo's Wii or virtual reality did show positive results even then--a lead well worth following.

Although emphasizing that further research is needed to see if the clear improvements caused by these cognitive exercise programs delay or perhaps in some cases prevent dementia, the researchers are encouraged. "Our research shows that brain training can maintain or even improve cognitive skills among older people at very high risk of cognitive decline," says neuroscientist Amit Lampit, who lead the study. "and it's an inexpensive and safe treatment."

With recent research also showing that structured physical exercises can also improve cognitive functioning in people with MCI (see my blog entry for 10/25/16), we can see the outline of safe and inexpensive interventions that may keep people's brains healthy and functioning well even as they age.

EXPERIMENTAL DRUG SHOWS PROMISE AGAINST ALZHEIMER'S DISEASE

With an ageing population, more than 5 million Americans suffering from Alzheimer's Disease, and with Alzheimer's now the sixth leading cause of death, finding an effective treatment is an urgent national goal.

Healthy vs diseased brain/Credit: Wikimedia

A new, still-experimental drug known as NTRX-07 shows promise towards that goal. Studies in mice whose brains have degenerative changes similar to those from Alzheimer's in humans show reduced inflammation and increased removal of amyloid plaques, both implicated in the devastating impacts of Alzheimer's.

Beta-amyloid plaques/Credit: vestque

Presenting their findings at the Anesthesiology 2016 Annual Meeting, lead researcher Mohamed Naguib and his colleagues reported that NTRX-07 enhanced the ability of microglial immune cells to reduce inflammation and clear toxic amyloid plaques from the brain.

"NTRX-07 uses a different mechanism than many other Alzheimer's drugs currently available," says Naguib, "as it targets the cause of the disease, not just the symptoms."

Of course, the path from a compound that shows promise in an animal model of a disease to a safe and effective human drug is a long and uncertain one--12 years on average. We can only hope that NTRX-07 or some other drug (such as a promising BACE1 inhibitor) that can prevent or cure Alzheimer's will run that gauntlet successfully and soon.

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3/14/19:  For an update on the promise of BACE1 inhibitors, navigate here.

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Pesticide Exposure, Cognitive Decline and Dementia Risk

When I worked as a neuropsychologist, I got to see first hand how even mild cognitive impairment could wreak havoc in a person's life. Of course Alzheimer's disease or other full-fledged dementias are even more destructive.

That's why a recently published study linking long-term pesticide exposure to cognitive impairment and, the researchers suspect, upping the risk of a person developing dementia, caught my attention.

You can read a summary of the research, which tracked over 600 French vineyard workers over time, on Suite101, by clicking here.

And, if you want, you can download the original article, in the journal Occupational and Environmental Medicine, at this URL.

Robert Adler