Amyloid aggregation may be a feature, not a bug, of the protein’s function. A bug-catching feature.
Researchers advanced the idea that amyloid aggregates may be a purposeful innate immune response to entrap microbes that have breached the blood-brain barrier, with such breaches increasing as the barrier gets leaky with age.
Aggregates of beta-amyloid are an early harbinger of trouble in the brains of Alzheimer’s disease patients. The general assumption has been that their aggregation is a malfunction that results from faulty processing of amyloid precursor processing.
“The data suggest that amyloid is not just junk in the brain,” co-corresponding author Rudolph Tanzi told BioWorld Today. And it may explain why, though Alzheimer’s disease is not, amyloid plaques are a universal feature of brains in individuals over the age of 40.
Tanzi is director of the Massachusetts General Hospital’s MIND Genetics and Aging unit.
Despite the blood-brain barrier’s efforts to keep them out, microbes – including yeast, chlamydia, spirochetes and herpes – manage to infect the brain, as they do every other organ.
Tanzi, co-corresponding author Robert Moir and their team first started to wonder whether plaques might have an immune function when they noted structural similarities between beta-amyloid and other antimicrobial peptides, and had previously published in vitro data supporting the idea that beta-amyloid had a role in innate immunity.
In their current experiments, published in the May 27, 2016, issue of Science, the team showed that high levels of amyloid beta protected mice against brain infections with the bacterium Salmonella typhimurium, and transgenic roundworms expressing amyloid beta were less susceptible to fungal infections.
Cell culture experiments showed that to have a protective effect, it was necessary for amyloid beta to aggregate.
The team was also struck by how rapidly the plaques formed in response to infection. Although some studies have suggested that amyloids can form very quickly, current dogma holds that by the time there are overt signs of brain dysfunction, amyloids have been accumulating for decades. (See BioWorld Today, Feb. 7, 2008.)
But “we saw amyloid precipitate overnight,” Tanzi said. And “you don’t need that many microbes to get in” to see an effect on plaque load.
In recent years, neuro-immune interactions and their contribution to both mental health and neurodegeneration have commanded an increasing amount of attention. (See BioWorld Today, Feb. 4, 2011, Feb. 6, 2015, and Jan. 22, 2016.)
Tanzi said his team’s work “fits nicely” with recent work showing that declining adaptive immunity may also play a role in the development of cognitive dysfunction, and that treating Alzheimer’s mice with PD-1 inhibitors, which were originally developed to unleash antitumor immune responses, improved cognitive performance in mouse models of dementia. (See BioWorld Today, Jan. 22, 2016.)
If Tanzi and his team are right, then one effect stimulating the adaptive immune system by way of PD-1 inhibition may be that it enables the adaptive immune response to fight brain infections, obviating some of the need for amyloid cages.
He said that it was “no surprise,” however, that general anti-inflammatories have been unsuccessful at slowing down cognitive decline. The best innate immune targets, in his opinion, are CD33, which controls microglial activation, and the microglial receptor TREM2.
Therapeutically, the work suggests that protecting the brain from the infections the plaques are fighting could slow down the onset of disease. Late-onset Alzheimer’s, which accounts for most cases, occurs in individuals over the age of 65. The average life expectancy of the U.S. population is just shy of 79 years – a bit higher for females, a bit lower for males – so pushing the disease onset back by even a few years would make an enormous difference to the overall incidence.
The Alzheimer’s fund, which supported the work now published in Science Translational Medicine, is planning to fund a brain microbiome initiative to gain a comprehensive understanding of the microbes that infect the human brain. In the long run, Tanzi said, those studies could inform prevention strategies for the disease.
“Maybe we can find the common offenders,” he said, “and possibly immunize against them.”