A New Treatment Candidate from Japan

Most of the love in Alzheimer's research has been going toward getting rid of beta amyloid plaques, but there are plenty of other ideas out there.  Especially since it's not clear how effective that strategy will turn out to be in improving cognition.  Recently, my friend Jim sent me an article from Tohoku University in Japan regarding a new treatment candidate that will begin human trials soon.  So far, it has produced promising results in mice, but we know how that goes.  The Japanese medical authorities have judged it to be safe for humans.

So here's the standard disclaimer on mouse models:  Mice are not people.  In the past, research with mice has generated a great deal of excitement until it was learned that a phenomenon with mice could not be replicated in humans.  Also, mice don't get Alzheimer's disease.  Instead, their genome (their DNA) can be modified to produce a disorder similar to Alzheimer's disease in humans, but it's not the same.  Often, mice are not very good models.

But you never know.

In this case, researchers administered a new molecule called SAK3 daily to some mice.  The mice had their genes edited to produce a disorder that mimics Alzheimer's disease.  With this disorder, amyloid plaques build up in the brains of the mice, and they experience cognitive decline in the same way that humans do.  This disorder can be used to model how different treatments will affect Alzheimer's disease in humans.  As we explained in Beating the Dementia Monster, mice with this disorder experience improved cognition when they get aerobic exercise.  So what happens when they take SAK3?

Obviously, the results so far have been promising, or I wouldn't have written this.

SAK3 appears to have a positive effect on a number of neurodegenerative diseases, not just Alzheimer's.  These include Parkinson's disease, Lewy body dementia, and Huntington's disease.  What these diseases have in common is that they all involve, in one way or another, misfolded proteins.  (Jim's son has done medical research on protein misfolding.) 

So what's the deal with misfolded proteins?  As you are certainly aware, proteins accomplish a LOT of tasks inside the brain as well as in the rest of the body.  They are constructed by taking specifically ordered chains of amino acids and folding them into a precises shape.  Two of the most important features of proteins that allow them to do their jobs is their shape and the arrangement of electrical charges on their surface.  Their shape is dictated by the sequence of charges in the amino acid chain, some of which attract and some of which repel other charges.  When the chain is jostled enough, attracting charges find each other, and the chain should fold up into a precisely formed protein molecule.

Except sometimes it doesn't. 

In the case of these diseases involving misfolded proteins in the brain, the defective proteins can't do their jobs, but they can cause trouble.  The biggest problem is that they can accumulate in places where they interfere with proper function of various brain cells and can even kill them.  In the case of Lewy body dementia, there is a presence of misfolded alpha-synuclein proteins.  Being misfolded, they can't perform their necessary function, which is to regulate certain neurotransmitters.

What can SAK3 do for us?  The researchers believe that it enhances the brain's natural ability to find and destroy misfolded proteins.  It the case of Alzheimer's disease, this should include, among other things, getting rid of amyloid plaques.

But even Aduhelm can do that.  What else can it do?  It appears to promote neuronal activity by increasing releases of acetylcholine and dopamine, two neurotransmitters found to reduce in activity in neurodegenerative disease.  This, of course, should improve cognition and perhaps even impede the advance of the disease.

Researchers are only now beginning to prepare for phase one studies, and so we are a long way from knowing more.  But, who knows?  Maybe SAK3 will turn out to produce dramatic results someday, overshadowing other drug treatments.