Amazingly similar: Misfolded amyloid beta and tau proteins can also accumulate in the brains of people with Down syndrome. As in Alzheimer’s dementia, these plaques can transfer their misfolding to other proteins – they are prions, as infectivity tests with cell cultures have now shown. This could explain why people with trisomy 21 often develop dementia early on. Although Alzheimer’s and this Down’s syndrome dementia have completely different causes, the neurodegenerative mechanisms in the brain are apparently similar.
Over a Alzheimer’s dementia nerve cells in the brain die, causing the mental abilities of those affected to deteriorate progressively. Misfolded amyloid beta (Aβ) and tau proteins, which build up as plaques and fibrils in the brain, are considered to be the triggers for the disease enrich and disturb the communication of the nerve cells. These misfolded proteins are now known in Alzheimer’s patients as prions classified as infectious proteins that can force normal proteins into the same misfolded shape.
Prions also in Down syndrome?
But Alzheimer’s is not the only neurodegenerative disease in which misfolded proteins are involved: it is also common in people with Down’s syndrome form of dementia could be due to such prions. About half of all people with trisomy 21 suffer from a progressive, Alzheimer-like breakdown of brain cells after the age of 40. And they also form plaques and fibrils from amyloid beta and tau proteins. However, it was previously unclear whether these proteins can transmit their misfolding.
For their study, researchers led by Carlo Condello from the University of California, San Francisco, therefore examined the infectious potential of protein plaques in Down’s dementia in more detail. To do this, they isolated amyloid and tau proteins from brain tissue samples from 28 deceased people with Down syndrome and 14 samples from healthy controls. They added the resulting protein solutions in various dilutions to human cell cultures.
Transmissible misfolding also in down dementia
The result: “With a few exceptions, we measured a robust infectivity of the amyloid beta and tau prions in almost all samples from Down patients,” report Condello and her colleagues. The misfolded proteins from the tissue samples also caused the beta-amyloid and tau proteins in the previously healthy cell cultures to misfold. “This confirms that dementia in Down syndrome is a double prion disease, like Alzheimer’s,” the team said.
In another test, the researchers compared the infectivity of the prions from brain samples from 26 Down patients with dementia with those from people with genetic, early-onset Alzheimer’s dementia. The cell culture tests showed comparable transferability rates for the misfolded amyloid beta and tau proteins. “Taken together, these data provide unequivocal evidence that Down’s syndrome, Alzheimer’s and familial Alzheimer’s all produce amyloid beta and tau prions, although they stem from very different causes,” the researchers state.
Explanation for dementia tendency in trisomy 21
The study also confirms a common hypothesis about how Alzheimer’s develops in the brain. Accordingly, the misfolded beta-amyloids appear early in the course of the disease and then initiate the formation of misfolded tau prions. “Consistent with this notion, we found solid levels of beta-amyloid prions but insignificant levels of tau prions in two of the youngest individuals with Down syndrome (19 and 25 years old),” the scientists report.
The fact that the disease starts from amyloid prions could explain why people with Down syndrome so often develop dementia: The gene for amyloid beta proteins is located on chromosome 21, which people with Down syndrome have in triplicate. As a result, they produce significantly more beta-amyloid than neurotypical people, putting them at greater risk of developing harmful protein plaques early in life.
Possibly treatable one day
By finding out more about the course of Alzheimer’s disease from people with Down syndrome, researchers benefit from one thing in particular: in trisomy 21, elevated prion concentrations can be detected at an early age. According to Condello’s colleague Stanley Prusiner, it is often difficult for people with Alzheimer’s to distinguish which changes in the brain are due to age and which are due to prion activity.
According to Condello, people with Down’s syndrome could therefore help to find out more about how Alzheimer’s develops and thereby possibly find a remedy that can prevent the onset of the disease from the outset. (Proceedings of the National Academy of Sciences, 2022, doi: 10.1073/pnas.2212954119)
Source: University of California-San Francisco, Proceedings of the National Academy of Sciences