Weak microglia may constitute a link between two hallmarks of Alzheimer’s disease—clumps of amyloid-β protein and tangles of tau protein. Microglia, the brain’s primary immune cells, are usually able to gather around amyloid clumps, effectively hemming them in. But according to scientists based at the Washington University School of Medicine, microglia may falter, allowing amyloid clumps to injure nearby neurons and create a toxic environment, one amenable to the spread of tau tangles.
Although amyloid plaques and tau tangles have been recognized as key steps in the development of Alzheimer’s disease, researchers have struggled to pin down the relationship between the two. By themselves, amyloid plaques do not cause dementia. Many people over age 70 have some amyloid plaques in their brains, including some who are as mentally sharp as ever. But the presence of amyloid plaques seems to lead inexorably to the formation of tau tangles—the true villain of Alzheimer’s.
“I think we’ve found a potential link between amyloid and tau that people have been looking for,” said David M. Holtzman, MD, a neurologist at the Washington University School of Medicine. “If you could break that link in people who have amyloid deposition but are still cognitively healthy, you might be able to stop disease progression before people develop problems with thinking and memory.”
Holtzman is the senior author of a study that appeared June 24 in Nature Neuroscience. The study, “TREM2 function impedes tau seeding in neuritic plaques,” suggests that microgliosis, the ability of activated microglia to congregate at the site of a lesion, may suffer if microglia express a dysfunctional version of a receptor protein called TREM2, or triggering receptor expressed on myeloid cells 2.
“Variants in TREM2 have been associated with increased risk for sporadic, late-onset Alzheimer’s disease,” the article’s authors wrote. “Here we show that germline knockout of Trem2 or the TREM2R47H variant reduces microgliosis around amyloid-β plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates.”
In their study, Holtzman and colleagues followed up on a key finding about TREM2: A mutated version of the TREM2 gene leaves people with weak and ineffective microglia. It also increases their risk of developing Alzheimer’s by twofold to fourfold.
To see where TREM2 might lead, the researchers used mice prone to developing amyloid plaques and modified in various ways their TREM2 genes to influence the activity of their microglia. The result was four groups of mice: two with fully functional microglia because they carried the common variant of either the human or mouse TREM2 gene, and two with impaired microglia that carried the high-risk human TREM2 variant or no copy of the TREM2 gene at all.
Then the researchers seeded the mice’s brains with small amounts of tau collected from Alzheimer’s patients. The human tau protein triggered the tau in mice to coalesce into tangle-like structures around the amyloid plaques.
In mice with weakened microglia, more tau tangle-like structures formed near the amyloid plaques than in mice with functional microglia. Further experiments showed that microglia normally form a cap over amyloid plaques that limits their toxicity to nearby neurons. When the microglia fail to do their job, neurons sustain more damage, creating an environment that fosters the formation of tau tangle-like lesions.
The researchers also showed that people with TREM2 mutations who died with Alzheimer’s disease had more tau tangle-like structures near their amyloid plaques than people who died with Alzheimer’s but did not carry the mutation.
“Even though we were looking at the brains of people at the end of the Alzheimer’s process rather than the beginning, as in the mice, we saw the same kind of changes: more tau in the vicinity of amyloid plaques,” Holtzman said. “I’d speculate that in people with TREM2 mutations, tau accumulates and then spreads faster, and these patients develop problems with memory loss and thinking more quickly because they have more of those initial tau tangles.”
The converse also may be true, Holtzman suggested. Powering up microglia might slow the spread of tau tangles and forestall cognitive decline. Drugs that enhance the activity of microglia by activating TREM2 already are in the pipeline. It soon may be possible to identify, using a simple blood test, people who have amyloid buildup but still lack cognitive symptoms. For such people, drugs that break the link between amyloid and tau might have the potential to halt the disease in its tracks.