Scattered evidence suggests that abnormal proteins act as “seeds” for transmitting neurodegenerative diseases, but controversy remains.
Freezing and Forming Process
When an ice crystal is dropped into a bottle of water near freezing point, an astonishing effect occurs: the liquid freezes rapidly and turns into a mass of ice.
At the molecular level, the ice crystal has a distinct shape – a lattice structure. As incoming water molecules join the network, the crystal grows.
Some researchers believe a similar process occurs in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. According to this theory, these diseases begin when a certain protein is misfolded or fails to take the correct shape to perform its intended role. This misfolded molecule captures normal copies of the protein, causing them to misfold in the same way, and over time, these rogue proteins accumulate into toxic aggregates that spread throughout the brain.
Transmission of Neurodegenerative Diseases Between People
Scattered studies over the past decade suggest that this may be possible, but such events appear to be extremely rare, and scientists are still trying to understand how pathogenic seeds arise and spread.
A small study in 2015 provided one of the first strong hints that misfolded beta-amyloid protein could be transmitted from person to person. When analyzing tissues from human corpses that died of Creutzfeldt-Jakob disease, researchers noted that six of them had significant accumulation of amyloid plaques in the brain. This substantial amyloid accumulation in the brains of individuals who died at a young age – between 36 and 51 – was surprising.
The team then investigated old stocks of growth hormone preparations and found them contaminated with beta-amyloid and another protein called tau, which is also a pathological marker for Alzheimer’s disease. When these preparations were injected into the brains of small mice designed to model Alzheimer’s disease, the preparations caused amyloid accumulation, while plaques failed to form in control mice that received pure growth hormone not derived from the bodies of individuals who died from Creutzfeldt-Jakob disease.
Transmission of Pathogenic Seeds from One Person to Another
Other reports have emerged of rare cases where amyloid seeds seem to have been transmitted between people. Some research focuses on the blockage of cerebral blood vessels by amyloid. Scientists believe this blockage increases the risk of small brain hemorrhages occurring in the brains of some Alzheimer’s patients who receive antibodies to remove amyloid.
These reports document cases of cerebral blood vessel blockages in a few adults who received transplants from bodies to close holes in the membranes surrounding the brain and spinal cord. Another study examined patient archives and medical literature and found cases of cerebral blood vessel blockages occurring at abnormally young ages in eight adults who underwent brain surgery during childhood or adolescence. These analyses raise the possibility that amyloid seeds might inadvertently enter individuals’ brains through contaminated surgical instruments.
Transmission of Pathogenic Seeds Through Blood Transfusions
A team of scientists focused their research – concentrating on blood transfusions and common neurosurgical procedures – and found 11 suspected cases of cerebral blood vessel blockages from beta-amyloid transmission through neurosurgeries, but no cases of blood transfusion during these procedures were found.
In September, a team at Karolinska University Hospital in Sweden published indirect evidence suggesting that blood transfusions could carry beta-amyloid. The scientists examined medical records for over a million people and found that individuals who received blood from someone who developed multiple small brain hemorrhages in the following years were three times more likely to experience brain bleeding compared to other individuals.
Effects
Transmission of Neurodegenerative Diseases
The interest in the transmission of diseases via pathogenic seeds continues to be punctuated by tragic news from time to time in the research community. Last month, the University of Barcelona announced that it had launched an investigation to trace the origins of unauthorized laboratory samples that may have contributed to the death of a biologist studying Creutzfeldt-Jakob disease.
Scientists are still struggling to understand the basic details of neurodegenerative disease transmission – for example, what triggers the occurrence of the initial misfolding. “It’s mysterious,” says Henrik Zetterberg, a neurochemist at the University of Gothenburg in Sweden.
Without technology to visualize misfolded proteins in the brains of living people, “we’ll never know,” says Yoker.
Yoker describes two possibilities: the first is that the formation of the initial aggregate is an extremely rare event – rare enough that it is unlikely to occur until the person is of advanced age. The second possibility is that protein aggregates form routinely even in young people but do not cause problems because the abnormal aggregates are cleared away by normal metabolic processes. However, this process slows down with age, making older individuals more susceptible to the accumulation of misfolded proteins that can spread and transmit diseases.
Advanced Imaging Techniques
With recent advances in advanced imaging technology known as cryo-electron microscopy, it is now possible to distinguish between the same protein when it adopts different conformations. Using cryo-electron microscopy to examine the tissues of deceased individuals who suffered from various diseases that lead to the accumulation of tau protein, researchers were able to discover different forms of misfolded tau associated with different diseases. Similarly, scientists found differences in the aggregation patterns of another protein called alpha-synuclein, which aggregates in Parkinson’s disease and other disorders.
Therapeutic Implications
Even when diseases are not yet detectable, such as young Alzheimer’s model mice that show no signs of accumulation yet, Yoker and colleagues showed that treatment with anti-amyloid antibodies significantly delayed the formation of amyloid plaques in the brains of these mice. These results provide indirect evidence that amyloid seeds were being cleared. The findings also align with recently approved amyloid antibody trials for Alzheimer’s disease, which show that removing amyloid from the brain can slow cognitive decline and suggest that intervening earlier could prevent amyloid buildup in the first place. “Prevention is the clear future,” says Larry Walker, a neuroscientist at Emory University, who co-authored a recent review on the topic with Yoker.
Initial Misfolding and Pathogenic Seeds
Many processes underlying neurodegenerative diseases remain mysterious. Even with numerous reports suggesting “infection” or transmission of organ diseases from one organism to another, “we don’t know what the infectious unit is,” says Yoker. For example, in the case of ice freezing, researchers are still questioning the nature of the “pathogenic seed.” Is it the “ice that has formed,” Yoker asks, “or are the invisible seeds still in that cup, and the ice is just the final product?”
Source: Scientific American
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