Watch Alzheimer's disease in action


Slowly and insidiously, they pile up in the brains of people with Alzheimer's disease.

Abnormal fragments of protein, known as β-amyloid, are superimposed to form the famous plaques reminding the German psychiatrist Alois Alzheimer of millet seeds when he saw them for the first time in the brain of a deceased patient in 1906. Then there are tau proteins, which normally help to stabilize the cellular skeleton of brain cells, but can begin to form entanglements with age, or when tau is defective.

The consequences are also well known: short-term memory loss usually occurs first, followed inevitably by mood swings, speech disorders, disorientation, and confusion. But the way in which these symptoms result from the two defective proteins and the entanglements and plaques they create has long remained obscure.

To study Alzheimer's brain tissue, neuroscientists had to fend for decades with slices of brain that they could manipulate in the laboratory. But how similar was it to what happens in the living and intact brains affected by Alzheimer's disease? About 15 years ago, the technology developed by neuroscientist Arthur Konnerth of the Technical University of Munich addressed this problem by enabling scientists to monitor the brain of mice in action.

Marc Aurel Busche, neuroscientist and psychiatrist at the Dementia Research Institute of the United Kingdom in London, who conducts research and advises patients with memory problems, was the first to apply this new technique to murine models. Alzheimer. This led to some surprising results, as reported in an article by Konnerth, Busche and two other colleagues from Annual Review of Neuroscience. This interview has been modified for its length and clarity.

Can you explain in basic terms how this technique allows us to see the brain in action?

What we really see is the calcium that gets into the cells, which happens every time a nerve cell goes off.

To make this visible, we are adding to the brain cells molecules that can bind to calcium and change their fluorescence when they do – a change that we can see or record with the help of. a microscope. For the studies we performed, we removed a very small portion of the cortex, the outer layer of the brain, so we could also visualize other areas, such as the hippocampus, which is important for memory .

New developments now allow us to create images of the hippocampus without removing the cortex. But in all cases, we could show that this deletion did not affect the behavior of the mouse or its level of activity.

A photo shows the cellular activity in the brain of a living mouse. In this murine model of Alzheimer's disease, a new imaging technique shows plaques of amyloid β and nerve cells nearby. Nerve cells near plaques can become hyperactive and interfere with communication between different regions of the brain. This hyperactivity led to the development of an anti-epilepsy drug for the treatment of Alzheimer's disease in mice. The drug is currently being tested in clinical trials in patients with Alzheimer's disease.

A new technique developed by Busche and Konnerth allows researchers to observe cellular activity in living animals. This image shows amyloid-β plaques (blue) in the brain of a murine model of Alzheimer's disease. The nerve cells (green) located near the plates can become hyperactive and affect the communication between the different regions of the brain. This hyperactivity led scientists to test a drug against epilepsy in the Alzheimer's mouse model. Clinical trials on Alzheimer's patients are underway.


Mice have brains quite different from ours and do not live as long. How to create a mouse model with a disease similar to Alzheimer's?

The development of mouse models is inspired by genetics. There are two forms of Alzheimer's: a sporadic form that only appears in the elderly and a family form that settles much earlier. In the second case, we often know exactly what genetic mutation is causing this mutation. We insert human genes carrying these mutations into mouse DNA so that the mice overproduce, in particular, the protein at the origin of amyloid-β.

The modified mice form amyloid plaques similar to those of human patients and also have memory disorders. It is important to mention, however, that these mice do not model all aspects of the disease. Many of them do not have an entanglement of tau, for example.

So, do they mimic the early form of Alzheimer's rather than the aging?

Yes, but with respect to clinical symptoms and how brain tissue is affected by the disease, the two are not very different. We therefore believe that mice are also useful for understanding the form associated with aging.

When you first applied this new imaging technique to examine the brain activity of a mouse overproducing amyloid-β human mouse, did you find what you were waiting for?

Our hypothesis was that the brain cells surrounding the amyloid plaques would be silent. But we found the opposite: many of these neurons were hyperactive. In the hippocampus, a crucial area for consolidation of memories, this hyperactivity appeared even before the formation of amyloid plaques.

This suggests that the hyperactivity is not due to the plaques themselves, but to the amyloid proteins in solution: the amyloid plaques tend to be surrounded by a soluble amyloid-β halo. In a reassuring way, the hippocampus has also been shown to be hyperactive in people with very early Alzheimer's disease.

The photo shows a slice of brain tissue from a mouse designed to have a condition related to Alzheimer's disease. Abnormal bits of β-amyloid protein are shown; these slip on each other, forming the plates that are the hallmark of the disease. Also shown are tau protein entanglements, which progressively dominate as the disease progresses.

This picture shows a slice of brain tissue of a murine model of Alzheimer's disease. Abnormal pieces of β-amyloid protein accumulate and slide over each other, forming the plaques (in pink) characteristic of the disease. Recent research suggests that β-amyloid makes nerve cells hyperactive. But this hyperactivity slowly attenuates with the multiplication of entanglements of tau proteins (indicated in green), which silence the neurons. The nuclei of the nerve cells are shown in blue.


Could this hyperactivity constitute an attempt on the part of healthy hippocampus cells to compensate for other cells already damaged by the disease?

It was the first assumption that many people had, that the hippocampus had to work a little harder to maintain its memory function. There is more and more evidence that this might not be true. In human studies, cognitive decline is faster in people with the highest levels of hyperactivity. This is the opposite of what one would expect if a more active hippocampus helped them to compensate for the damage. And in the mouse, it has been shown time and time again that hyperactive neurons are actually detrimental to normal function.

Can we say that rather than work harder, they only make more noise?

Yes. If some cells are active all the time, they can mask the significant signals of others.

Could this hyperactivity explain some of the symptoms seen in the early stages of Alzheimer's disease?

A certain degree of consistent activation of the hippocampus and cortex is important for successful storage and recovery of memory. Hyperactivity alters this communication and mice with hyperactive hippocampus are altered in cognitive and behavioral tests. However, when we treat them to reduce hyperactivity, communication is normalized and their behavior improves.

The hyperactivity can also disrupt the activity and coordination of the brain regions in what is called the "default mode network," a number of interconnected brain areas that are active when we are n & # 39; Let's not perform any task, when our mind is left to wander. This network plays an important role, for example, in forming memories about oneself, such as the time and place where we had lunch yesterday – called self-referential memories.

I think it's important to mention that aside from memory problems, many people with Alzheimer's also suffer from depression, attention deficit or sleep disorders – symptoms that we do not have. have not used to pay much attention. It is not clear if these are all manifestations of the disease or early risk factors for developing it, but it is possible that some of them are also related to changes in the network mode. by default. Depression, for example, is affected by the same circuit; it has many self-referential aspects.

The link with sleep problems is interesting and worrying. What do we know about this?

I started looking at sleep in mice after finding that my patients at the memory clinic often complain of sleep disorders. If we examine the electrical activity of the human brain or mouse brain using EEG [electroencephalography, a recording of electrical activity in the brain]we can see different slow waves crossing the brain during the deepest phases of sleep. It turns out that these waves are less consistent and therefore probably altered in Alzheimer's.

Sleep could be one of the main drivers of Alzheimer's disease progression, because we now know that it is affected very early. Many studies show that the proteins that are the cause of the disease are released in greater numbers when we are awake and that sleep can help eliminate them. In this sense, sleep hygiene – to minimize the impact of factors such as activities or drinks that can interfere with your sleep – is important. But again, we still do not know for sure that sleep deprivation directly contributes to the development of Alzheimer's disease. It could also be that sleep disorders are only an early symptom of the disease.

The image shows brain scans with amyloid plaque accumulation in three patients with low, intermediate and elevated plaque levels in an area of ​​the prefrontal cortex. Three electroencephalographic (EEG) images of slow-wave sleep activity in the three patients are also shown. Slow-wave sleep is important for consolidating newly formed memories; it is disrupted in patients with Alzheimer's.

Brain scans (top) reveal an accumulation of amyloid plaque – a plaque load – in three patients with low, intermediate, and high levels in an area of ​​the prefrontal cortex. The slow-wave sleep activity (below), which is important for the consolidation of newly formed memories, is disturbed in the same way in patients, reveals an electroencephalogram (EEG) measurement.

Can sleeping pills be part of the solution?

The problem with sleeping pills is that they often suppress the normal rhythm of sleep. Most of the medications we use usually alter the physiology of normal sleep – some of them look more like anesthesia.

This is not the type of normal sleep that is healthy for you. They can provide considerable relief, for a short time, if a person does not really sleep, but it is not a permanent solution.

Have the results of hyperactivity inspired new pharmacological approaches to Alzheimer's disease?

We believe that hyperactivity could also contribute to the epileptic-like activity – or epileptiform – described for the first time in mice that overproduce human β-amyloid by Lennart Mucke's laboratory at UC San Francisco. Initially, many clinicians were skeptical, but it turns out that this activity occurs in 15 to 25% of Alzheimer's patients. There are now experiments with levetiracetam, a medicine against epilepsy, which has been shown to be effective in reducing epileptiform activity in the amyloid-β mouse model while improving their cognition. It is currently undergoing large-scale Phase III clinical trials to determine if this can help early in the treatment of Alzheimer's disease.

Many other medical trials on Alzheimer's disease to prevent formation or to reduce the concentration of amyloid-β ended early. What could they have missed?

First of all, there are still some treatments targeting amyloid in the phase III trials, and I really hope that some of them could turn out to be positive. But I think recent setbacks show that the mice we use are incomplete models and that the other protein, tau, could make a difference.

Many groups have shown that we can basically cure these amyloid-producing mice. But this is not effective in patients because they also have tau protein. The current thinking in the field, which is reflected in the design of clinical trials, is that there is no particular interaction between amyloid-β and tau. But research conducted in recent years, including ours, show that there is a synergy between the two proteins and that amyloid-β could worsen the effects of tau protein.

In your last study, you tried to highlight how the two proteins interact. It shows that when brain neurons of mice are designed to overproduce human tau and amyloid-β, they are not overactive, as they are in amyloid-only mice, but are silenced. This seems rather contradictory – how could these results be reconciled?

I think it's really important to watch how the disease evolves in space and time. It is indisputable that nearly one-fifth of patients have early epileptiform activity – that the hippocampus is hyperactive in many patients with early Alzheimer's disease – and that, when they interact with the outside world, their default mode network often does not default, it would normally do so. So there is plenty of evidence of increased activity.

At the same time, we have long known that the brain is silent later on during the course of the disease – studies show a decrease in metabolism and blood flow.

We currently have a simple model based on what we see in the patients' brains. The amyloid plaques appear first and as long as we have mainly β-amyloid protein, we expect an increase in hyperactivity. Then, when tau begins to spread, it will gradually become dominant and more and more nerve cells will be silenced. This silence can be reversible – in mice, at least, these cells are not dead, but at rest. However, to prevent or even fix this situation, I think we will most likely have to target both proteins at the same time.


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