Washington University Study Shows Alzheimer’s Progression May Hinge on Newfound Amyloid & Tau Link


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. However, Washington University School of Medicine researchers states microglia may falter, allowing amyloid clumps to injure nearby neurons and hence create a toxic environment, one open to the spread of tau tangles.

By themselves, amyloid plaques don’t cause dementia reports Genetic Engineering & Biotechnology News. However, amyloid plaque presence appears to lead inexorably to the formation of tau tangles—the ultimate villain in Alzheimer’s. David M. Holtzman, MD, and neurologist at the Washington School of Medicine reports “I think we’ve found a potential link between amyloid and tau that people have been looking for.”

The Study

Titled “TREM2 function impedes tau speeding in neuritic plaques” offers 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 called TREM2, or triggering receptor expressed on myeloid cells 2.

In their study, Holtzman and colleagues followed up on a key finding of 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.

Lead Research/Investigator

David M. Holtzman, MD, and neurologist at the Washington School of Medicine