The aging brain frequently harbors multiple protein pathologies that contribute to Alzheimer's, Parkinson's and other neurodegenerative diseases. But how do these problematic proteins interact with each other, and could these interactions inform future therapies?
Researchers at TGen, part of City of Hope , are answering some of these questions with the help of a unique mouse model that combines different mixtures of dementia-related proteins including amyloid-beta, alpha-synuclein and tau.
"Alzheimer's disease is the most common neurodegenerative dementia. It's defined by two main types of brain changes: amyloid plaques and tau tangles. But other changes can also appear, including alpha‑synuclein," said John Fryer, Ph.D. , inaugural director of TGen's Center for Accelerated Nanotherapeutics and the senior author of the study. "Alpha‑synuclein can show up alongside Alzheimer's disease, or it can be the main feature in conditions like Lewy body dementia or mixed‑pathology dementia."
Benjamin Rabichow, Ph.D. , a former graduate student in the Fryer lab, and his colleagues designed a new viral delivery system to express alpha-synuclein and tau pathologies in the brains of mice — before and after amyloid plaque deposition. In a study published today in the journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association , this mixed mouse model revealed some intriguing interactions.
"I think the field has some appreciation for needing to be able to study all three [proteins] in the same system because the reality is that's often the case for many patients," said Rabichow, the study's first author who is now a postdoctoral fellow in pathology at the University of California, San Diego. "We found, for instance, that alpha-synuclein and tau induced after plaque deposition increased levels of the defective versions of these proteins that lead to toxic aggregations in the brain. The added proteins also exacerbated amyloid-related behaviors such as hyperactivity and anxiety in the mice."
When the researchers induced alpha-synuclein and tau in mice before amyloid plaque deposition, however, the induction still led to robust levels of pathological proteins. These mice also developed mild hyperactivity and anxiety behaviors, albeit at a slower rate than animals with amyloid plaques.
The findings suggest that the timing of alpha-synuclein and tau pathologies affects how the proteins interact with amyloid, even if the mechanics behind the interaction are still unclear.
"One possible avenue is that amyloid creates some burden on the cellular machinery in the brain that controls protein homeostasis," said Rabichow, "so that the brain is less equipped to clear these additional pathologies."
Surprisingly, the researchers also found that tau pathology, independent of other dementia-related proteins, led to a hyper-inflammatory response in non-neuronal cells in certain tracts of white matter.
In patients, clinicians look for amyloid and neurofibrillary tangles in the brain, but it's not commonplace to look in regions where these neurons might be connecting with these white matter fibers. The findings suggest that looking more closely at these white matter tracts in human brains could be important.
"One of the next steps in the research will be to test the mouse model against some recently approved Alzheimer's treatments," said Fryer, who also serves as director of TGen's Immunology and Microbiome Division. "We want to see how these therapies react in more of a real-world situation with the pathologies that patients actually have, which is these complex mixed pathologies."
The National Institute of Neurological Disorders and Stroke (NS110435)) funded this research.
