Discovery May Indicate New Treatment Approach for Common Neurodegenerative Disorders – ScienceDaily


The brains of people with Down syndrome develop the same tangles and neural plaques associated with Alzheimer’s disease, and they often show signs of the neurodegenerative disorder in their 40s or 50s. A new study by researchers at the University of California, San Francisco, shows that these tangles and plaques are driven by the same amyloid-beta (Aß) and tau prions that they showed are behind Alzheimer’s disease in 2019.

Prions start out as normal proteins that become deformed and self-replicating. They spread through tissues like an infection by forcing normal proteins to take on the same distorted shape. In both Alzheimer’s syndrome and Down syndrome, as Aß and tau prions accumulate in the brain, they cause neurological dysfunction that often manifests as dementia.

Tau tangles and Aß plaques appear in most people with Down syndrome by the age of 40, according to the National Institute on Aging, with at least 50% of this population developing Alzheimer’s disease as they age.

The new study, published November 7, 2022, in the Proceedings of the National Academy of Scienceshighlights how a better understanding of Down syndrome can lead to new insights into Alzheimer’s disease as well.

said Stanley Prusner, the study’s senior author, who was awarded the Nobel Prize in 1997 for his discovery of prions.

Down syndrome is the most common neurodegenerative disease among young people 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 there is one called APP, which codes for one of the major components of beta-amyloid. With an extra copy of the gene, people with Down syndrome produce an excess amount of the APP protein, which may explain why amyloid plaques appear early in life.

Young minds give 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. Having previously shown that these neurodegenerative features are triggered by prions in Alzheimer’s disease, the researchers wanted to see if the same abnormal 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, Brusner, MD, director of the UCSF Institute, said it can be difficult to distinguish changes in the brain since aging and any changes that result from prion activity. Neurological Diseases, part of the Weill Institute of Neurosciences.

“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 get a better picture of the early process of disease formation, before the brain becomes complicated by all the changes that occur during aging.” “And ideally, you want treatments that address these early stages.”

Using a variation on the new test they used in the Alzheimer’s study, the team looked at donated tissue samples from deceased people with Down syndrome, which they obtained from biobanks around the world. From 28 samples from donors between the ages of 19 and 65, the researchers were able to isolate measurable amounts of Aß and tau prions in almost all of them.

New insights could lead to prevention

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

“The field has long been trying to understand what the intersection between these two diseases is,” said lead author Carlo Condello, PhD, who is also a member of the UCSF Institute for Neurodegenerative Diseases. “The case of Down syndrome supports the idea; now you have this extra chromosome driving the Aß, and there is no tau gene on the chromosome. So, by overexpressing the Aß, you start producing tau.”

Condello said this and other insights from studying the brains of people with Down syndrome will lead to a much better picture of how prions begin to form in the first place.

The researchers said whether brain tissue from Down syndrome will prove to be the final model for developing treatments for Alzheimer’s disease remains to be seen. While the two disorders share many similarities in the pathobiology of prions, there are some differences that may be limited.

However, the researchers said that studying the plaques and tangles in Down syndrome is a promising avenue for identifying specific prions that arise in the very early stages of the disease process. This insight could open new avenues for not only treating Alzheimer’s disease but possibly even preventing it.

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

Authors: Additional UCSF authors on the study include Allison Maxwell, Department of Pharmaceutical Chemistry, and Erica Castillo, Atsushi Aoyagi, and William Seely, of the UCSF Weill Institute of Neurosciences. For other authors, please see the study.

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 philanthropy. For a complete list, please see the study.



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