Prions are misfolded versions of a protein that can spread like an infection by forcing normal copies of that protein into the same self-propagating, misfolded shape. According to new research led by the University of California, San Francisco (UCSF), Alzheimer’s disease is a double-prion disorder in which amyloid beta and tau proteins together destroy the brain. Using novel lab tests, UCSF researchers Stanley Prusiner and Carlo Condello and their colleagues were able to detect and measure specific, self-propagating prion forms of amyloid beta and tau proteins in brain tissue of 75 Alzheimer’s patients.
“I believe this shows beyond a shadow of a doubt that amyloid beta and tau are both prions, and that Alzheimer’s disease is a double-prion disorder,” Dr. Prusiner said.
“The fact that prion levels also appear linked to patient longevity should change how we think about the way forward for developing treatments for the disease.”
In the study, the team combined two recently developed laboratory tests to rapidly measure prions in human tissue samples: a new amyloid beta detection system and a tau prion assay.
Unlike earlier animal models that could take months to reveal the slow spread of amyloid beta and/or tau prions, these cell-based assays measure infectious prion levels in just three days, enabling the researchers to effectively quantify for the first time the levels of both tau and amyloid beta prions in processed extracts from post-mortem brain samples.
The scientists applied the technique to autopsied brain tissue from over 100 individuals who had died of Alzheimer’s disease and other forms of neurodegeneration, which was collected from repositories in the United States, Europe, and Australia.
In assays comparing the samples from Alzheimer’s patients with those who died of other diseases, prion activity corresponded exactly with the distinctive protein pathology that has been established in each disease: in 75 Alzheimer’s disease brains, both amyloid beta and tau prion activity was elevated; in 11 samples from patients with cerebral amyloid angiopathy, only amyloid beta prions were seen; and in 10 tau-linked frontotemporal lobar degeneration samples, only tau prions were detected.
Another recently developed bioassay for alpha-synuclein prions only found these infectious particles in the seven samples from patients with the synuclein-linked degenerative disorder multiple system atrophy.
“These assays are a game-changer,” said UCSF Professor William DeGrado, co-author of the study.
The most remarkable finding of the study was the discovery that the self-propagating prion forms of tau and amyloid beta are most infectious in the brains of Alzheimer’s patients who died at a young age from inherited, genetically driven forms of the disease, but much less prevalent in patients who died at a more advanced age.
In particular, when compared to measurements of overall tau buildup — which is known to increase with age in Alzheimer’s brains — the study authors found a remarkable exponential decline in the relative abundance of the prion forms of tau with age.
When the researchers plotted their data, they saw an extremely strong correlation between tau prions and patients’ age at death: relative to overall tau levels, the quantity of tau prions in the brain of a patient who died at age 40 were on average 32 times higher than in a patient who died at 90.
The study raises a number of questions that will need to be addressed by future studies, including whether differences in prion infectivity could explain the long-standing mystery of why Alzheimer’s progresses at such different rates in different patients.
Other open questions include whether higher prion levels in brain samples from younger patients are linked to the early onset of the disease or how quickly it progressed, and whether lower prion levels in older brains reflect less ‘infective’ prion variants or instead some ability of these patients’ brains to dispose of misfolded proteins.
“The evidence that prion forms of amyloid beta and tau play a specific role in Alzheimer’s disease also raises questions on current approaches to Alzheimer’s diagnosis, clinical trial design, and drug discovery,” the scientists said.
“We have recently seen many seemingly promising Alzheimer’s therapies fail in clinical trials, leading some to speculate that we have been targeting the wrong proteins,” Dr. Condello said.
“But what if we just haven’t been designing drugs against the distinctive prion forms of these proteins that actually cause disease? Now that we can effectively measure the prion forms of amyloid beta and tau, there’s hope that we can develop drugs that either prevent them from forming or spreading, or help the brain clear them before they cause damage.”
The study was published in the journal Science Translational Medicine.
Atsushi Aoyagi et al. 2019. Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Science Translational Medicine 11 (490): eaat8462; doi: 10.1126/scitranslmed.aat8462