PNAS: Accident! Like Alzheimer's disease, Down syndrome is a biprion disease

People with Down syndrome develop neurodegenerative tangles and plaques associated with Alzheimer's disease in their brains and often show signs
of this neurodegenerative disease by the age of forty and fifty 。 In 2019, researchers from the University of California, San Francisco in the United States have pointed out that Alzheimer's disease is caused by β amyloid (Aß) and tau prions (Science Translational Medicine, 2019, doi:10.
1126/scitranslmed.
aat8462; see Biovalley News: Science Subissue: Alzheimer's disease is actually a biprion disease)
。

Now, in a new study, the researchers confirm that neurodegenerative tangles and plaques that appear in the brains of people with Down syndrome are driven
by the same Aß and tau prions.
The findings were published in the Nov.
15, 2022 issue of PNAS as "Aβ and tau prions feature in the neuropathogenesis of Down syndrome.
"

Prions start as normal proteins, become malformed and self-propagate
.
They spread
through tissues like a viral infection by forcing normal proteins to adopt the same misfolded shape.
In Alzheimer's disease and Down syndrome, with the accumulation of Aß and tau prions in the brain, they lead to neurological dysfunction, often manifested as dementia
.

According to the National Institute on Aging, most people with Down syndrome develop tau tangles and Aß plaques by age 40, and at least 50% of this population will develop Alzheimer's disease
as they age.
The new study highlights how a better understanding of Down syndrome can also lead to a new understanding
of Alzheimer's disease.

Dr.
Stanley Prusiner, co-corresponding author of the paper and director of the UCSF Institute for Neurodegenerative Diseases, said, "There are two diseases--- Down syndrome and Alzheimer's disease, which have completely different etiologies, but we see the same disease biology
.
It's really amazing
.
Prusiner was awarded the Nobel Prize
in 1997 for discovering prions.

Down syndrome is the most common neurodegenerative disease in young Americans, while Alzheimer's disease is the most common disease
in adults.
Down syndrome occurs due to the presence of an extra copy of chromosome
21.
Among the many genes on this chromosome is a gene called APP, which codes for one of the main components of
Aß.
Because of the presence of an extra copy of the gene, people with Down syndrome develop an excess of APP, which may explain why they develop Aß plaques
early in life.

A younger brain provides clearer understanding

Aß plaques and tau tangles
are known to be present in both Down syndrome and Alzheimer's disease.
Earlier, the authors had learned that these neurodegenerative traits were triggered by prions in Alzheimer's disease, and they wondered if the same abnormal proteins
were present in the brains of people with Down syndrome.

Prusiner said that while these plaques and tangles in the brains of Alzheimer's patients have been extensively studied, it can be a challenge
to discern which changes in the brain come from increasing age and which come from prion activity.

"Because we see the same plaque and tangled pathology at a much younger age in people with Down syndrome, studying their brains allows us to better understand the early processes of disease formation, after all, all the changes in the brain are more complex
at an older age," he said.
Ideally, people want therapies
that can treat the disease in its early stages.
”

Cell bioassay experiments detected Aβ and tau prions
in brain samples from patients with Down syndrome.
Image from PNAS, 2022, doi:10.
1073/pnas.
2212954119
.

The authors took an improved version of a novel detection they used in their Alzheimer's disease research, looking at donated brain tissue samples from people who died of Down syndrome, which they obtained
from biobanks around the world.
In 28 brain samples from donors aged 19 to 65, they were able to isolate measurable amounts of Aß prions and tau prions in almost all of the samples
.

New insights may develop preventive measures

These findings confirm not only the involvement of prions in neurodegeneration in Down syndrome, but also the formation of Aß-driven tau tangles and amyloid plaques, which have previously been proposed but not proven
.

Dr.
Carlo Condello, co-corresponding author and a member of the UCSF Institute for Neurodegenerative Diseases, said, "The field has long sought to understand what the intersection between these two diseases is
.
These cases of Down syndrome confirm this idea; Today, people with Down syndrome have this extra chromosome that drives Aß, which does not have the tau gene
.
Therefore, it is indeed initiating the production
of tau by increasing the expression of Aß.
”

Condello said this new insight, along with other insights gained from studying the brains of people with Down syndrome, will give us a better understanding of how prions begin to form
in the first place.

The authors say it remains to be seen whether brain tissue from people with Down syndrome will prove to be
the ultimate model for developing treatments for Alzheimer's disease.
While the two diseases share many similarities in prion pathology, there are also some differences that may create limitations
.

However, the authors say that studying plaques and tangles in Down syndrome is a promising avenue to identify specific prions
that appear at the earliest stages of the disease process.
This new insight opens up new prospects
not only for treatment but 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 meaningful point in time and really stop the formation of these larger brain lesions," Condello said.
(Biovalley Bioon.
com)

Resources:

Carlo Condello et al.
 Aβ and tau prions feature in the neuropathogenesis of Down syndrome, PNAS, 2022, doi:10.
1073/pnas.
2212954119.