Aging brains often harbor multiple protein pathologies that contribute to Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. But how do these problematic proteins interact, and could these interactions potentially inform future treatments?
Researchers at TGen, part of City of Hope, are trying to answer some of these questions using a unique mouse model that combines a diverse mixture of dementia-related proteins, including amyloid-beta, alpha-synuclein and tau.
Alzheimer’s disease is the most common neurodegenerative dementia. It is defined by two main types of brain changes: amyloid plaques and tau tangles. However, other changes may also appear, such as alpha-synuclein. Alpha-synuclein sometimes appears with Alzheimer’s disease and is a key feature of conditions such as Lewy body dementia and mixed dementia. ”
Dr. John Fryer, founding director of TGen’s Center for Accelerated Nanotherapy and senior author of this study
Dr. Benjamin Labichaud, a former graduate student in the Fryer lab, and his colleagues designed a new viral delivery system to express alpha-synuclein and tau pathology in mouse brains before and after amyloid plaque deposition. In a study published today in the journal Alzheimer’s Disease and Dementia: Journal of the Alzheimer’s Association, This mixed mouse model revealed several interesting interactions.
“I think there’s some understanding in this field that you need to be able to study all three (proteins) in the same system, because the reality is often that’s the case in many patients,” said Labichaud, lead author of the study and now a postdoctoral fellow in pathology at the University of California, San Diego. “For example, we found that alpha-synuclein and tau induced after plaque deposition increased levels of defective versions of these proteins that cause toxic aggregation in the brain. The added proteins also worsened amyloid-related behaviors such as hyperactivity and anxiety in the mice.”
However, when the researchers induced alpha-synuclein and tau in mice before amyloid plaque deposition, they still induced high levels of the pathological proteins. These mice also developed mild hyperactivity and anxiety behavior, although at a slower rate than animals with amyloid plaques.
The findings suggest that the timing of α-synuclein and tau pathology influences protein-amyloid interactions, even though the mechanisms behind the interactions are still unclear.
“One possible way is that amyloid puts some strain on the brain’s cellular machinery that controls protein homeostasis, thereby reducing the brain’s ability to clear these additional pathologies,” Dr. Labichaud said.
Surprisingly, the researchers also found that tau pathology causes an exaggerated inflammatory response in non-neuronal cells in specific regions of white matter, independent of other dementia-related proteins.
Clinicians look for amyloid and neurofibrillary tangles in patients’ brains, but they don’t commonly look at the areas where these neurons may connect with white matter fibers. The findings suggest that it may be important to take a closer look at the white matter tracts of the human brain.
“One of the next steps in our research is to test mouse models against some of the recently approved Alzheimer’s disease drugs,” said Fryer, who is also director of TGen’s Division of Immunology and Microbiome. “We want to see how these treatments respond in a more realistic setting to the conditions that patients actually have: these complex, mixed conditions.”
The National Institute of Neurological Disorders and Stroke (NS110435)) funded this study.
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Translational Genomics Institute
Reference magazines:
Ravicho, B.E. others. (2026). Amyloid exacerbates tau and alpha-synuclein pathology, behavioral deficits, and neuroinflammation in a mixed dementia model. Alzheimer’s disease and dementia. DOI: 10.1002/alz.71639. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71639
