Protein-Busting Drug Could be New Era For Alzheimer’s Therapy

Israeli scientists have developed a new drug to treat Alzheimer’s disease following a recent discovery about how people lose their memories. 

The creators of the drug, which is currently undergoing preclinical trials, say it could potentially be life-changing for people living with Alzheimer’s. 

The disease – the most common type of dementia, which affected up to 40 million sufferers worldwide in 2023- is known to have no cure. Furthermore, there are still no agreed-upon causes of the disease, even though it was first diagnosed in 1906.

The ailment breaks down the neural synapses – the channels through which neurons (nerve cells that send messages to the whole body) communicate in the brain. This atrophies key areas of the brain and ultimately causes a significant loss of brain functionality.   

The new drug from Herzliya-based startup MemoryPlus blocks two proteins in the brain from interacting and causing the breakdown of neural synapses, something which exacerbates memory loss. 

The development came after the researchers discovered high levels of PTEN, one of the two proteins, in the brains of late Alzheimer’s sufferers. 

A different protein, amyloid beta, is believed to be one the primary causes of Alzheimer’s, as it causes what is called amyloid plaque to build up in the brains of people with the disease. The plaque forms in the spaces between the nerve cells, which disrupts cell function in memory – and most treatments for Alzheimer’s focus on this plaque. 

MemoryPlus, however, focuses on disrupting the interaction between PTEN and another protein called PSD-95. 

The company was founded in 2018 by Dr. Shira Knafo of Ben-Gurion University of the Negev; Prof. Gal Ifergane, director of the neurology department at Soroka Medical Center in Be’er Sheva; and Ben-Gurion University business school alum Ehud Netta. 

Two years earlier, Knafo’s Molecular Cognition Lab discovered that as well as causing cancer when it mutates, the PTEN protein also impairs brain functioning both when there is a surplus of it and when it interacts with PSD-95 in the synapses. 

“Until now, the PTEN protein was only known in relation to cancer. We found out it’s also doing something unrelated. It’s doing something to the brain function and plasticity and learning and memory,” says Knafo.

Knafo’s lab had examined the postmortem brains of people who had had Alzheimer’s disease and found high levels of the PTEN protein in the neural synapses. 

“When there’s too much of the PTEN protein, it becomes toxic to the synapses. What we saw is that in Alzheimer’s disease, the [surplus] PTEN protein enters the synapses and causes them to be much weaker. When they become weak, they can’t pass information that well, and then you see loss of brain function and memory because the synapses are considered to be the place of information storage.”

Furthermore, PTEN often interacts in the synapse with PSD-95, which is a scaffolding protein that helps relay information between the cell membrane and nucleus more quickly. 

Both proteins are important when functioning independently, but when they interact with each other, they can cause synaptic depression that leads to more memory loss. 

Knafo’s lab developed a peptide (the building blocks of proteins) that would interact with PSD-95 and thereby prevent PTEN from doing so. 

The peptide not only blocks the harmful interaction between PTEN and PSD-95, Knafo says, but it can also prevent the toxic buildup of PTEN and preserve the neural synapses and cognitive function. 

Drugs (such as memantine and cholinesterase inhibitors) are given to Alzheimer’s patients to boost messenger chemicals in the brain crucial to memory and learning, which helps reduce symptoms of the disease. However, Knafo says that unlike MemoryPlus’ treatment, these drugs cannot prevent the destruction of further nerve cells.  

Major pharma companies such as US-based Biogen and Eli Lilly are also developing new drugs for Alzheimer’s, but these treatments target amyloid beta and Knafo does not see them as competitors.

“It’s true that they got rid of amyloid beta, but they didn’t improve memory,” she says. 

“We are working on completely different aspects of Alzheimer’s. Amyloid beta can stay in the brain as long as we can bypass it. We are working on the synapses.” 

The peptide is administered orally and is currently undergoing preclinical trials in the UK, China, Hong Kong, and Israel. 

Knafo explains that peptides have the advantage of being able to target very specific proteins, which means that they tend to have less side effects. However, she says that peptides can be less stable and more easily degraded by enzymes in the blood.

The company is also looking at small molecules as a new way of delivering the treatment, after screening thousands of synthetic small molecules in a five-year long study with the University of Hong Kong. 

“Small molecules can enter the brain more easily, but they may have some side effects. We currently have five different synthetic small molecules that do the same thing as a peptide. Once we test them and find the right one, we will take it all the way to clinical testing.”

Both the peptide and small molecules would work in the same way, by binding to PSD-95. This would prevent PTEN from binding to it and damaging the neural synapses as a result.

“We’re not trying to cure Alzheimer’s yet, but improve the symptoms,” says Knafo. 

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