Whether or not someone develops Alzheimer’s disease could be the result of a key transition in microglial activity, according to new research published recently in Nature Medicine. Researchers led by Mark Fiers and Bart De Strooper at the VIB-KU Leuven Center for Neuroscience and University College London, in collaboration with Muna Therapeutics, found that microglia switch from an early inflammatory response in the presence of amyloid plaques to an antigen-presenting state that coincides with the development of tau tangles.
Fiers told DDN that the work “started from an observation that has mystified the field for years: Many people have a brain full of amyloid but never get dementia.” The research team wanted to use spatial transcriptomics techniques to specifically study what goes on in the brain around amyloid plaques. Their work revealed that the postmortem brains of octogenarians and centenarians who did not show cognitive symptoms of Alzheimer’s disease — despite having the classic pathology in their brains — diverged in their patterns of microglial resilience.
The findings point to a novel therapeutic strategy that could target this microglial shift instead of focusing only on clearing amyloid plaques. “These findings open new opportunities to target microglial states,” said Niels Plath, Chief Scientific Officer of Muna Therapeutics, in the press release. “We are excited to continue this journey and understand the causal role of microglial transitions leading to the identification of novel therapeutic approaches to delay or prevent disease progression.”
Finding the turning point
In the new work, the researchers used spatial transcriptomics and single-nucleus RNA sequencing on the superior frontal cortex of the postmortem brains and mapped the transcriptional sites onto local amyloid and tau pathology. Specifically, they identified six tissue domains that represented a continuum from homeostasis to neurodegeneration. Between the domains representing amyloid plaque pathology and tau tangle pathology, the researchers found the turning point where microglia shifts from the early inflammatory state, associated with early plaque-induced gene (PIG) programs, to the late antigen-presenting state that leads to neurodegeneration, associated with late PIG programs.
The researchers showed that the brains of cognitively healthy octogenarians did not have microglia that switched to the antigen-presenting state. However, reaching that state did not automatically mean progression to Alzheimer’s disease; in cognitively healthy centenarians, the later microglial program was activated but did not lead to tau tangle accumulation.
“We assumed the late antigen-presenting state was a bad sign, a marker that things were going downhill, and then there it is in people who stayed sharp into their hundreds, without the local [tau pathology],” Fiers told DDN. “That forced us to rethink it: The state itself isn't the problem, it's more about how it gets set up or read out.”
He added that it could be directly a result of the microglial signaling, or it could be how the neurons respond to it that leads to neurodegeneration. Answering that question is now part of what the researchers plan to study next. Fiers said that their team would like to “pin down whether the microglial state transition actually drives tau propagation, responds to it, or runs alongside it — the kind of causality we simply can't establish from cross-sectional tissue.”
Targeting the transition
In future work, Fiers said that their team also plans to investigate how genetic risk is related to the microglial processes. With more research, that information could potentially be used to develop a biomarker that indicates whether someone is at risk of these microglial state transitions leading to neurodegeneration.
For those who are at risk, new therapies directed at stopping the late-stage microglial transition before it happens could become a novel therapeutic strategy. This could include targeting the SPP1 (secreted phosphoprotein 1) gene that regulates immune responses or proteins expressed on microglia like TREM2 (triggering receptor expressed on myeloid cells 2) or CSF1R (colony stimulating factor 1 receptor).
However, the presence of the late microglial program in centenarians suggests that transitioning to this state does not guarantee neurodegeneration. If future work reveals how the brains of these individuals are able to fend off neurodegeneration despite the late microglial transition, new therapeutic strategies could follow their lead as well.
For now, the new study suggests rethinking therapies that only focus on clearing amyloid plaques or tau tangles. “The textbook story is amyloid leads to tau leads to neurodegeneration, all in a line, but that just doesn't account for the people who don’t seem to follow that path,” said Fiers.
