Alzheimer’s disease (AD) affects over 44 million people the world over. But now, neurologist Jack Jhamandas and his team have found two short peptides which, on daily injection into mice with symptoms of AD for just five weeks, led to a significant improvement. Not only did they have better memory, but they showed a reduction in the accumulation of beta-amyloid, the harmful protein that characterizes the condition, and lower levels of the markers of brain inflammation.
U of A neurologist Jack Jhamandas led a team that found a new treatment significantly improved memory in mice with Alzheimer's disease. The researchers are now developing a drug that could eventually be used to treat human patients. Image Credit: Jordan Carson
Beta-amyloid accumulation may predate the clinical features of AD by 15-25 years. Thus many researchers have tried to reduce amyloid levels either by increasing the rate at which it is removed from the brain or by blocking its formation via enzyme inhibition, but without success. Many such projects have found brain receptors through which beta-amyloid appears to act, such as p75NTR receptor, or SCARA1/2, but none which block all three routes of brain damage: loss of neurons, inflammation, and vascular damage. The amylin receptor (AMY) appears to fulfil this criterion, being found abundantly on neurons, blood vessels, and inflammatory brain cells called microglia.
What was done in this study?
In the study, published in Scientific Reports, the researchers built on their earlier discovery of the peptide called AC253. This compound was tested in mice with AD. It was found to block the attachment of beta-amyloid to a brain cell receptor called the amylin receptor, and thus inhibit its toxic effects, as shown by an improvement in spatial memory. However, it is difficult to administer this compound because it doesn’t cross the blood-brain barrier in large amounts, and is quickly broken down in the blood. The dosage must therefore be massively increased, pushing up the amounts required for efficacy and increasing the difficulty of administration, besides enhancing the chances of an immune reaction.
One way out is to convert the formulation into a pill rather than an injectable form. The complex structure of AC253 makes this difficult as well.
Instead, the team devised an ingenious solution. They cleaved the compound into smaller amylin peptides, or chains of 12-14 amino acids, and tested each for its anti-amyloid activity in old mice which showed signs of AD. In this way, they found two short peptides that had the same effects as the larger compound. In particular, the researchers identified a segment that was common to both peptides, namely, SQELHRLQTY.
How do these peptides act?
These peptides, like the parent compound AC253, acted as antagonists at the AMY receptor. They were also resistant to protein breakdown, and crossed the blood-brain barrier easily when injected into the abdominal cavity, to localize in the hippocampus, which is crucial in memory. These peptides protected the brain against beta-amyloid injury, and normalized the AD-associated impairment of the memory-associated long-term potentiation of nerve impulses in the hippocampus. They improved memory testing results, and reduced the level of inflammation in the brain.
These effects appear to be mediated via the blockade of AMY receptors. For instance, inhibition of microglial AMY receptors reduce the activation of the inflammasome NLRP3. This reduces the secretion of inflammatory chemicals in the surrounding brain tissue, which offers another mechanism for lower amyloid production. In addition, these peptides increase the rate of outflow of amyloid beta from the brain, which also contributes to a lower level of amyloid after treatment. These marked changes all occurred within a relatively short span of treatment.
A very important additional finding was that treatment with these peptides brought about improvement in mice which were showing signs of well-established AD in the brain as well as in their behavior. This is unique in that most therapies fail to affect the progress of AD once it has begun to manifest clinically. Peptides also have fewer off-target effects.
Small molecules are easy to administer, inexpensive to make and cross the blood-brain barrier more rapidly. For this reason, the team resorted to computational tools and artificial intelligence to come up with a new small molecular drug based on these peptides. This can be taken orally, and is similar in size and structure to the medications used for medical conditions like high blood pressure. An optimized version is being developed to enable human trials to be conducted.
The work so far has taken about two decades, building step upon painstaking step to come up with the right solution. However, says Jhamandas, “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.”
Short amylin receptor antagonist peptides improve memory deficits in Alzheimer’s disease mouse model. Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang & Jack Jhamandas. Scientific Reports, volume 9, Article number: 10942 (2019). https://doi.org/10.1038/s41598-019-47255-9. https://www.nature.com/articles/s41598-019-47255-9