A case of dementia can be called Alzheimer's disease when the presence of "sticky" amyloid plaques and neurofibrillary tangles is observed in the brain. Forget the tangles for now, but the sticky amyloid molecules clump onto brain cells, apparently killing them. This is the generally operational hypothesis, and it is the basis for the strategy of using monoclonal antibodies to remove the plaques from the brain. It is the mode of operation for treatment with aducanumab, donanemab, and others.
But we said in Beating the Dementia Monster that not everyone agrees on the actual role of the plaques in the disease. What if the plaques are actually a form of protection for the cells? Wouldn't that mean that removing them is a big mistake?
On April 14, Nature Immunology published research suggesting something like that. The research involved removing certain genes from mice to manipulate which proteins are constructed in the brain. Pretty much everything that happens with respect to metabolism in the brain is executed by proteins, and removing different proteins from the picture help explain what they were there to do in the first place.
In Beating the Dementia Monster, we explained that microglia are cells that constitute the brain's immune system. The brain has special needs with respect to immunity, so it gets its own system, isolated from the body's normal immune system. The microglia then run the brain's immune system, and they appear to play a role in Alzheimer's disease.
By knocking out different genes in mice (and thus preventing their corresponding proteins from being constructed), the researchers found that certain proteins participate with microglia in compacting amyloid into plaques. So maybe the amyloid is only sticky after being treated by the microglia. Without this treatment, the amyloid molecules continue as wisps along blood vessels to some, so far unexplained, end. One hypothesis is that the microglia are acting as trash compactors to gather and store the amyloid in a less toxic form.
(Recall our previous cautions that mice are not people, and what works with mice may not work with people.)
If so, this is a true game-changer. It would upend much of the direction of the search for an effective treatment for Alzheimer's disease, since so much focus has been on the importance of removing the plaques. While the plaques may figure in killing the cells, we would first need to recognize their benevolent purpose.
We have developed several treatments that remove amyloid plaques from the brain, but their outcomes with respect to improved cognition have been disappointing. There has been great pressure on the FDA to approve aducanumab as a treatment for Alzheimer's disease, but we discussed earlier that the FDA's advisory council has recommended that it not be approved, at least not yet. Those promoting aducanumab have increased pressure on the FDA (for example), but the advisory council recently doubled down on their conclusion that the antibody's effectiveness has not been demonstrated.
You can find a more in-depth discussion here.
No comments:
Post a Comment