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Reviving “awake neurons” may solve drowsiness in Alzheimer’s

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Drowsiness or lethargy during the day is a common sign of Alzheimer’s disease, but what causes it and is there any way to treat sleep disturbances driven by neurodegeneration?

There is no lack of sleep to blame for the lethargy that many people with Alzheimer’s have, but rather the degeneration of a type of neuron that keeps us awake, according to a previous study. That study also found that tau protein is behind that neurodegeneration.

This new study based on the previous findings points to possible treatments that could help these patients feel more awake.

The data came from people who were patients at UC San Francisco’s Memory and Aging Center and agreed to have their sleep monitored with an electroencephalogram (EEG) and give their brains to science when they died.

The ability to correlate sleep data with microscopic pictures of their post-mortem brain tissue was crucial in answering a question that scientists had been debating for years.

“We were able to prove what our previous research had been pointing to—that in Alzheimer’s patients who need to nap all the time, the disease has damaged the neurons that keep them awake,” says Senior author Dr. Lea Grinberg

“It’s not that these patients are tired during the day because they didn’t sleep at night,” notes Grinberg. “It’s that the system in their brain that would keep them awake is gone.”

Patients with other neurodegenerative disorders, such as progressive supranuclear palsy (PSP), who were also included in the study, experienced the opposite effect. Patients with damage to the neurons that cause them to feel weary are unable to sleep and suffer from sleep deprivation.

After uncovering a set of neurons that keep us awake and are affected in Alzheimer’s from the outset of the disease, Grinberg’s team formulated the notion that Alzheimer’s patients were having problems remaining awake.

“You can think of this system as a switch with wake-promoting neurons and sleep-promoting neurons, each tied to neurons controlling circadian rhythms,” adds Joseph Oh, one of the lead authors. “Finally, with this post-mortem tissue, we’ve been able to confirm that this switch, which is known to exist in model animals, also exists in humans and governs our sleep and awake cycles.”

“Extremely Smart Neurons” Disrupted by Tau Proteins

Oh describes these neurons as “extremely smart” because they can produce an array of neurotransmitters and can excite, inhibit, and modulate other nerve cells. 

“It’s a small number of neurons but their computational capabilities are incredible,” Oh said. “When these cells are affected by disease, it can have a huge effect on sleep.” 

To determine what’s contributing to the degradation of these neurons in Alzheimer’s, the researchers looked at the brains of 33 patients with Alzheimer’s, 20 with PSP, and 32 volunteers who’d had healthy brains through the end of life.  

The team measured the amounts of two proteins often associated with the neurodegenerative process—beta amyloid and tau. Which of the two is more involved in disrupting sleep has been a long-disputed question, with most researchers crediting the sleep problems to beta-amyloid accumulation.

During sleep, the brain clears out the beta amyloid that accumulates during the day. When we can’t sleep, it builds up. So, Neylan said, since the PSP patients never sleep, she expected to see lots of the protein in their brains. 

“But it turns out that they have none,” he said. “These findings confirm with direct evidence that tau is a critical driver of sleep disturbances.” 

In patients with PSP, said Grinberg, this understanding turned the treatment paradigm on its head. 

“We see that these patients can’t sleep because there is nothing telling the “awake” neurons to shut down,” she said. “Now, rather than trying to induce these people to sleep, the idea is to shut down the system that’s keeping them awake.”

Clinical Trial is Giving Patients Hope

That idea is currently being tested in a clinical trial of patients with PSP, using a treatment that specifically targets the overactive ‘awake’ system that keeps these patients from sleeping. This approach contrasts with the traditional trial-and-error treatment with sleep medications. 

At the helm of that trial is Christine Walsh, PhD, the study’s other lead author, who has also worked on the study for a decade. Noting that PSP and Alzheimer’s are at opposite ends of the sleep-disturbance spectrum, she said she expects the research to lead to new ways of treating sleep disturbances driven by neurodegeneration.
 
Treatments for Alzheimer’s could be adjusted depending on the patient’s needs, bumping up the “awake” system while tamping down the “sleep” system, said Walsh, who along with Grinberg, is a member of the UCSF Weill Institute for Neurosciences. 

The PSP trial is still underway, and Walsh is highly optimistic that this new approach will have better results than current medications for people with either condition. Based on the findings of the study published today, she said, “We’re even more hopeful that we can actually make a difference in the lives of these patients.”

Source: What makes Alzheimer’s patients drowsy?

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