Rare mutation found to stop spread of toxic tau clumps in Alzheimer’s
Mimicking effects of APOE variant may protect against Alzheimer's: Study
A rare variant in the APOE gene, known as the Christchurch mutation or APOE3ch, can protect against the development of Alzheimer’s disease by stopping the spread of toxic clumps of the tau protein in the brain, a new study suggests.
The findings may have implications for better understanding Alzheimer’s underlying mechanisms and, potentially, developing new treatments.
“Any protective factor is very interesting, because it gives us new clues to how the disease works,” David Holtzman, MD, the study’s senior author at Washington University School of Medicine, in St. Louis, said in a university news story.
“If we can find a way to mimic the effects of the APOE Christchurch mutation, we may be able to stop people who already are on the path to Alzheimer’s dementia from continuing down that path,” Holtzman said.
The study, “APOE3ch alters microglial response and suppresses A[beta]-induced tau seeding and spread,” was published in the journal Cell.
Rare mutation found in woman in Columbia
Alzheimer’s is marked by toxic clumps of two types of protein in the brain: amyloid-beta and tau. It’s thought that amyloid-beta clumps build up first in the earliest stages of the disease, often before any symptoms are apparent.
Then tau starts forming clumps, which leads to more pronounced damage. “When this happens, cognitive impairment soon ensues,” Holtzman said.
While the causes of Alzheimer’s remain incompletely understood, genetics are thought to play a major role in whether or not the disease will develop. In some instances, specific causes of familial Alzheimer’s have been identified.
Such was the case for a large family in Columbia, which saw half of its members develop early-onset Alzheimer’s — at a median age of 44 — due to a mutation in the PSEN1 gene that is linked to rapid accumulation of amyloid-beta clumps.
However, there was a single exception. One woman carrying this mutation retained full cognitive function until her 70s, and only then did she experience some very mild cognitive decline.
Genetic analyses revealed she had two copies of a rare variant in the APOE gene. This gene, which has three common versions or alleles, strongly influences Alzheimer’s risk.
The APOE4 allele is one of the strongest risk factors in Alzheimer’s, while the APOE2 allele is associated with a lower Alzheimer’s risk relative to the most common APOE3 allele. This woman specifically had an APOE3 variant called APOE3ch.
Further, distinct analyses of this woman’s brain before and after she died showed high levels of toxic amyloid-beta clumps — but very little tau burden.
“One of the biggest unanswered questions in the Alzheimer’s field is why amyloid accumulation leads to tau [burden],” Holtzman said.
“This woman was very, very unusual in that she had amyloid [burden] but not much tau [burden] and only very mild cognitive symptoms that came on late,” Holtzman said. “This suggested to us that she might hold clues to this link between amyloid and tau.”
The scientists said this case raised the possibility that APOE3ch might protect against Alzheimer’s in the presence of strong genetic risk factors by influencing the activity of amyloid and/or tau.
But it was not possible to conclude this definitively from a single person’s experience.
Experiments conducted in mouse model of Alzheimer’s
Now, Holtzman and colleagues conducted a battery of experiments in a mouse model of Alzheimer’s that overproduces clumping-prone amyloid-beta forms. Their aim was to test how the APOE3ch mutation might confer protection against Alzheimer’s.
The mouse models were injected with human tau protein into their brains. In the presence of toxic amyloid-beta aggregates, or plaques, this is known to trigger a disease-associated process of toxic clumping that spreads to other parts of the brain.
That process, however, was reduced substantially in mice carrying the APOE3ch mutation in both copies of the APOE gene. These mice also showed less amyloid-beta burden than those carrying the normal APOE3 allele.
Importantly, according to the researchers, these beneficial effects were still dependent on the presence of toxic amyloid-beta clumps. In their absence, the APOE3ch variant had no effect on tau spreading.
If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments.
Further experiments suggested that the gene variant’s protective effects were associated with increased activation of microglia, the brain’s resident immune cells, around amyloid plaques.
Microglia also serve as the brain’s sanitation workers — these cells are capable of ingesting and destroying molecular debris. In mice carrying APOE3ch, microglia surrounding amyloid clumps were more active, so they could destroy more tau aggregates and ultimately reduce its toxicity.
“We found that APOE3ch facilitates microglia clustering around plaques with enhanced [debris-clearing activity], suggesting an elevated microglial activation state in the presence of [amyloid-beta] plaques due to APOE3ch that could contribute to attenuated [tau burden],” the researchers wrote.
Holtzman put it in simpler terms.
“These microglia are taking up the tau and degrading it before tau [burden] can spread effectively to the next cell,” Holtzman said. “That blocked much of the downstream process; without tau [burden], you don’t get neurodegeneration, atrophy [brain shrinkage] and cognitive problems.”
While these results don’t definitively prove that the APOE3ch variant prevented Alzheimer’s for the woman in the original report, they provide a plausible biological explanation for how this mutation might protect against Alzheimer’s.
Further, they suggest these mechanisms might be targeted to treat or prevent the disease in the future.
“If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments,” Holtzman said.