The brains of people with Down syndrome (DS) develop the same neurodegenerative tangles and plaques that are associated with Alzheimer’s disease (AD), and individuals with DS commonly exhibit signs of the neurodegenerative disorder in their forties or fifties. A new study from researchers at UC San Francisco (UCSF) has now shown that the tau tangles and plaques in DS are driven by the same amyloid beta (Aß) and tau prions that are implicated in AD.

The study demonstrates how a better understanding of DS could lead to new insights into the development of AD. “Here you have two diseases—Down syndrome and Alzheimer’s disease—that have entirely different causes, and yet we see the same disease biology. It’s really surprising,” said Stanley Prusiner, MD, the study’s senior author, who was awarded the Nobel Prize in 1997 for his discovery of prions.

Prusiner and colleagues reported on their latest findings in PNAS, in a paper titled “Aβ and tau prions feature in the neuropathogenesis of Down syndrome,” in which they concluded, “In agreement with others, we propose that research in people with DS may help clarify sAD pathogenesis, given that both neuropathology and prion infectivity closely resemble that found in sAD [sporadic AD], the predominant form of AD.”

Down syndrome is caused by an extra copy of chromosome 21, and is the most common chromosomal disorder in humans, the authors wrote. “In the United States, there are ∼400,000 people with DS and ∼5.4 million worldwide.” Individuals with DS who live beyond age 40 years commonly develop a progressive dementia that is similar to Alzheimer’s disease.

Prions begin as normal proteins that become misshapen and self-propagate. They spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape. It’s been known for some time that Aß plaques and tau tangles are present in both Down syndrome and Alzheimer’s. In these disorders, Aß and tau prions accumulate in the brain, and cause neurological dysfunction that often manifests as dementia. “In the last two decades, numerous studies have shown that both Aβ and tau proteins adopt pathogenic, self-propagating conformations characteristic of prions,” the team noted. “Prions induce the misfolding of additional copies of the naïve protein (e.g., Aβ or tau) in a self-perpetuating process that spreads within and between neural cells …”

Tau tangles and Aß plaques are evident in most people with DS by age 40, according to the National Institute on Aging, with at least 50% of this population developing AD as they age. Among the many genes on chromosome 21 is APP, which codes for one of the major 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 early in life. “Aβ plaques and tau NFTs are considered a common neuropathological feature in most individuals with DS older than 40,” the authors continued. “The anatomical distribution and biochemical properties of Aβ plaques and NFTs are similar to those of AD, which are thought to contribute to progressive dementia and related biomarker changes in approximately two-thirds of aged people with DS.”

Having shown previously that the neurodegenerative features of AD are provoked by prions, the researchers wanted to know whether the same aberrant proteins were present in the brains of people with Down syndrome. There have been extensive studies of these plaques and tangles in the brains of people with Alzheimer’s disease, but it can be challenging to discern which changes in the brain are from old age and which are from prion activity, noted Prusiner, director of the UCSF Institute for Neurodegenerative Diseases, part of the Weill Institute for Neurosciences. “Because we see the same plaques-and-tangles pathology 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 has become complicated by all the changes that go on during aging,” he said. “And ideally, you want therapies that address these early stages.”

Employing a variation on the novel assay they used in their Alzheimer’s study, the team looked at donated tissue samples from deceased people with Down syndrome, which they obtained from biobanks around the world. Of the 28 samples from donors aged 19 to 65 years old, the researchers were able to isolate measurable amounts of both Aß and tau prions in almost all of them. “We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays,” they explained. “In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions.”

The results also confirmed not only that prions are involved in the neurodegeneration seen in Down syndrome, but that Aß drives the formation of neurofibrillary tangles containing the tau protein as well as amyloid plaques, a relationship that had been suspected but not proven. “The field has long tried to understand what the intersection is between these two pathologies,” said first author Carlo Condello, PhD, also a member of the UCSF Institute for Neurodegenerative Diseases. “The Down syndrome case corroborates the idea; now you have this extra chromosome that’s driving the Aß, and there’s no tau gene on the chromosome. So, it’s truly by increasing the expression of Aß that you kick off production of the tau.”

The authors further wrote, “Our findings demonstrate that the brains of people with DS feature both Aβ and tau prions, which appear to be indistinguishable from the two prions that accumulate in both the sporadic and familial forms of AD … The finding that Aβ and tau prions are positively correlated in DS and AD agrees well with genetic and experimental studies arguing that Aβ prions arise early in AD pathogenesis and that these prions initiate subsequent tau prion formation.”

The new insights offered by the newly reported study results, and the findings of other research 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, said Condello. The investigators also acknowledged that it remains to be seen whether the Down syndrome brain tissue will prove to be the ultimate model for developing treatments for Alzheimer’s. While the two disorders share many similarities in their prion pathobiology, there are some differences that may be limiting. “Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined,” they stated.

Nevertheless, the researchers said, studying the plaques and tangles in DS is a promising route to identifying the specific prions that arise at the very earliest stages of the disease process. That insight could open new vistas on not only treating but perhaps even fending off AD.

“If we can understand how this neurodegeneration begins, we are one big step closer to being able to intervene at a meaningful point and actually prevent these large brain lesions from forming,” Condello said. The authors further stated, “… because the brains of long-lived people with DS exhibit increased prion infectivity, we posit that more molecular studies for people with DS are needed to better understand how age-dependent pathogenic mechanisms in DS cause a divergent prion phenotype from sAD. The outcome of such work may have important implications for developing drugs that are more aptly tailored to improve quality of life for people with DS.”

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