Training the brain's immune system to recognize and clear toxic material is rapidly emerging as an promising way to put the brakes on Alzheimer's disease. Unfortunately researchers haven't been clear on how this method of protection operates on a cellular level.
An international team of researchers analyzed brain samples taken from people who had died with Alzheimer's, some of whom had also received approved Alzheimer's immunotherapy treatments. The therapies encourage cleaning cells called microglia to attack the clumps of amyloid-beta proteins that are thought to be involved in neurodegeneration.
Microglia responses to amyloid beta can lead to inflammation, which in turn risks damage to brain tissues. The researchers wanted to know why immunotherapy turned microglia into ruthless cleaning machines in some cases but not others.
"Our study is the first to identify the mechanisms in microglia, the brain's immune cells, that help limit the spread of amyloid in certain brain regions following treatment with amyloid-targeting drugs," says neuroscientist David Gate, from the Northwestern University Feinberg School of Medicine.
The team observed microglia not only remove amyloid beta protein clumps but also contain the inflammatory response necessary for this removal, helping the brain recover.
These insights were obtained in part through a technique called spatial transcriptomics, which can highlight activity of targeted genes. The genes linked to supercharged microglia included APOE and TREM2, both of which have been identified as being related to Alzheimer's disease in earlier studies.
While it's early days for this field of research, the findings from the study could potentially lead to new ways to put a stop to amyloid beta build-up and the development of Alzheimer's symptoms.
"A long-standing question in the field of Alzheimer's therapeutics is if we coax these immune cells into removing the amyloid, are they just always going to be in that amyloid-removal mode?" says Gate.
"The answer we found is no, they can remove the amyloid and then go back to being good and appear to actually help the brain heal."
Putting the body's own defense force through a better training scheme is always going to be preferable to introducing additional chemicals into the brain, and the researchers hope that the disease brakes can be applied before Alzheimer's gets a grip.
And while the immunotherapies we mentioned at the top are approved by regulators and can help battle Alzheimer's disease, there's a lot of room for improvement in terms of increasing their success rate and reducing the risk of associated side effects.
"I think everyone agrees that, although these drugs are becoming more effective, they ultimately do not cure Alzheimer's disease patients," says Gate.
"These drugs stimulate the immune cells of the brain to remove amyloid beta, but we believe that the data in our publication can be utilized to make these drugs work even better."
The research has been published in Nature Medicine.