Although an effective treatment or cure for Alzheimer’s disease has remained elusive, new research is coming in regularly that brings scientists one step closer every day. Jack Jhamandas, University of Alberta Distinguished University Professor and neurologist, may have taken an even bigger step.
Although an effective treatment or cure for Alzheimer’s disease has remained elusive, new research is coming in regularly that brings scientists one step closer every day. Jack Jhamandas, University of Alberta Distinguished University Professor and neurologist, may have taken an even bigger step.
Jhamandas and his research team identified two short peptides, which are strings of amino acids, that significantly improved the memory in mice with Alzheimer’s when injected. The peptides also decreased accumulation of beta-amyloid and decreased brain inflammation, both hallmarks of the disease.
It had previously been found that a molecule called AC253 can block the toxic effects of beta-amyloid. AC253 blocks beta-amyloid from attaching to specific brain cell receptors. However, AC253 is quickly metabolized in the blood and isn’t very effective at reaching the brain. Treatment with the compound requires massive doses to be effective, with is both impractical and dangerous.
Jhamandas’ approach was to cut AC253 into pieces in an attempt to develop smaller peptides that blocked beta-amyloid the same way AC253 did. The team eventually identified two shorter sections of AC253 that have similar effects to the larger molecule.
Working with Lorne Tyrell and Michael Houghton, leveraging computer modeling and artificial intelligence, they found a small-molecule drug similar to drugs currently used to treat high blood pressure or cholesterol, that they are now developing. They hope to optimize and manufacture an oral version of the molecule so they can test it in human clinical trials.
“In the mice that received the drugs, we found less amyloid plaque buildup and a reduction in brain inflammation,” Jhamandas said. “So this was very interesting and exciting because it showed us that not only was memory being improved in the mice, but signs of brain pathology in Alzheimer’s disease were also greatly improved. That was a bit of a surprise for us.”
In recent periods, as the beta-amyloid theory of Alzheimer’s moves to the back burner, more and more attention is being paid to the role of the immune system and inflammation in the disease. In July, Rudy E. Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital, published a study in the journal Neuron that identified crosstalk communication between TREM2 and CD33, two genes that play a role in inflammation and Alzheimer’s disease. CD33 carries the genetic code for receptors on microglia cells. TREM2 has the opposite effect, shutting down microglia’s ability to promote neuroinflammation. Basically, CD33 switches on neuroinflammation and TREM2 turns it off.
And recently, Pfizer came under fire because in 2015 several researchers analyzing hundreds of thousands of insurance claims noted that patients receiving the company’s Enbrel, a powerful anti-inflammatory, seemed to have a reduced risk of Alzheimer’s disease, by about 64%. The company chose not to pursue a trial or to publish the data, and it was only in February 2018 that the observation went public.
Although a very long ways from a cure or treatment, Jhamandas’ research does provide more support for understanding the role of neuroinflammation and beta-amyloid in Alzheimer’s disease. The study was published in the journal Scientific Reports.
“This has been 15, 20 years of painstaking and incremental work,” Jhamandas said. “And it’s like building a house: you put one brick down, then you put another brick on top of that, and pretty soon you have a foundation and then you have a house. Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I’m very excited that we are really on to something here.”
