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Discovery may point to new therapeutic approach for common neurodegenerative diseases – ScienceDaily

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The brains of people with Down syndrome develop the same neurodegenerative tangles and plaques associated with Alzheimer’s disease, and often show signs of the neurodegenerative disorder in their forties or fifties. A new study by researchers at the University of California, San Francisco shows that these tangles and plaques are caused by the same amyloid beta (Aß) and tau prions that they showed in 2019 to be behind Alzheimer’s disease.

Prions start out as normal proteins that deform and self-propagate. They spread through tissues like an infection, forcing normal proteins to assume the same misfolded shape. In both Alzheimer’s and Down syndrome, Aß and tau prions accumulate in the brain and cause neurological dysfunction that often manifests as dementia.

According to the National Institute on Aging, at least 50% of this population develops Alzheimer’s disease as they age.

A new study published on November 7, 2022 in Proceedings of the National Academy of Scienceshighlights how a better understanding of Down syndrome may also lead to new insights into Alzheimer’s disease.

“Here you have two diseases – Down syndrome and Alzheimer’s disease – that have completely different causes, but we see the same biology of the disease. It’s really amazing,” said Stanley Prusiner, MD, senior author of the study, who was awarded the 1997 Nobel Prize year for the discovery of prions.

Down syndrome is the most common neurodegenerative disease among young adults in the United States, while Alzheimer’s disease is the most common among adults.

Down syndrome is caused by an extra copy of chromosome 21. Among the many genes on this chromosome is one called APP, which codes for one of the main components of amyloid beta. With an extra copy of the gene, people with Down syndrome produce excess APP, which may explain why they develop amyloid plaques at an early age.

Young brains paint a clearer picture

It has been known for some time that Aß plaques and tau tangles are present in both Down syndrome and Alzheimer’s disease. The researchers, having previously shown that these neurodegenerative features are triggered by prions in Alzheimer’s disease, wanted to know if the same aberrant proteins were present in the brains of people with Down syndrome.

Although there have been extensive studies of these plaques and tangles in the brains of people with Alzheimer’s disease, it can be difficult to determine which brain changes are caused by aging and which are caused by prion activity, said Prusiner, director of the UCSF Institute. of Neurodegenerative Diseases, part of the Weil Institute of Neurology.

“Because we see the same pathology of plaques and tangles at a much younger age in people with Down syndrome, studying their brains allows us to gain a more complete picture of the early development of the disease, before the brain becomes complicated by all the changes that occur during aging.” he said. “And ideally you want treatments that target those early stages.”

Using a variant of the new assay they used in Alzheimer’s disease research, the team looked at donated tissue samples from deceased people with Down syndrome that they obtained from biobanks around the world. From 28 samples from donors aged 19 to 65, the researchers were able to isolate measurable amounts of Aß and tau prions in almost all of them.

New understanding may lead to prevention

The results support not only that prions are involved in the neurodegeneration seen in Down syndrome, but also that Aß drives the formation of tau tangles as well as amyloid plaques, a link that has been suspected but not proven.

“The field has long been trying to understand what the intersection between these two pathologies is,” said lead author Carlo Candela, Ph.D., also a member of the UCSF Institute of Neurodegenerative Diseases. “The Down syndrome case supports this idea; now you have an extra chromosome driving Aß and no tau gene on the chromosome. So by actually increasing the expression of Aß, you start the production of tau.”

This understanding and other findings from studying the brains of people with Down syndrome will lead to a much better picture of how prions start to form in the first place, Candela said.

Whether Down syndrome brain tissue will become the ultimate model for developing Alzheimer’s treatments remains to be seen, the researchers said. Although the two diseases share many similarities in their prion pathobiology, there are some differences that may be limiting.

Still, studying Down syndrome plaques and tangles is a promising way to identify specific prions that occur early in the disease process, the researchers said. This understanding could open up new perspectives not only for treatment, but perhaps even for the fight against Alzheimer’s disease.

“If we can understand how this neurodegeneration begins, we’re one big step closer to being able to intervene at a significant point and actually prevent these large brain lesions from forming,” Candela said.

Authors: Additional UCSF study authors include Alison Maxwell of the Department of Pharmaceutical Chemistry and Erica Castillo, Atsushi Aoyagi, William Seeley of the UCSF Weill Institute of Neuroscience. For other authors, see research.

Funding: This work was supported by NIH grants P01AG002132, P30AG066519, AG023501, and AG019724, and DHA grants HU311661-040066323 and HU0001-19-2-000, along with other institutes and philanthropies. For a complete list, see the study.

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