Amyloid β (Aβ) is a fragment of the APP protein that, when it misfolds and clumps together, forms amyloid plaques, one of the main hallmarks of Alzheimer’s disease. These plaques accumulate in the brain as the disease progresses. As these proteins build up, they eventually clump together to form fibrils. To effectively halt the progression of those fibrils, neurological researchers need to observe how they grow at the molecular level. Now, for the first time, a collaborative research group has achieved just that. Read on for more information on this groundbreaking research, published in the Journal of the American Chemical Society, which could dramatically impact the way medical professionals treat Alzheimer’s disease.
Observing Amyloid Plaque Fibril Growth in Real Time
When Aβ proteins clump together to form fibrils in the brain, it interferes with brain function. This worsens over time as the fibrils become more numerous throughout the brain. Unfortunately, the exact growth mechanisms of Aβ fibrils have remained unclear — until now, thanks to new research from teams at the Exploratory Research Center on Life and Living Systems and the Institute for Molecular Science of the National Institutes of Natural Sciences, as well as Nagoya City University, Nagoya University, and the University of Tsukuba.
The researchers collaborated to use advanced high-speed atomic force microscopy (HS-AFM) to observe Aβ fibril growth at the molecular level. The team made these observations in real time, which helped establish patterns in fibril formation.
The team made numerous observations, including one startling realization about the composition of Aβ fibrils. Each fibril is composed of two thin strands called protofilaments, which grow in an alternating pattern with individual Aβ molecules adding to the ends of each strand. The team discovered that, when the ends of the protofilaments align, fibril growth temporarily stops. The high-resolution molecular observations allowed the research team to document this growth-pause mechanism, which was an entirely new finding. This could be a breakthrough moment in understanding how Alzheimer’s disease progresses and potentially slowing its advancement by tapping into the “pause” signal.
Key Antibody Could Unlock Secret to Slowing Amyloid Plaque Development
The team made another notable discovery surrounding the role of a specific antibody in the brain. The antibody, labeled 4396C, selectively binds to the ends of the fibrils during the aforementioned paused state. When the antibody binds, the fibril is essentially “locked” into its paused state; in other words, further growth is impossible. This could have sweeping implications for the treatment of Alzheimer’s disease. For example, if researchers can duplicate the role of this antibody, it might influence cognitive decline in its tracks. The team plans to further investigate this antibody, along with other hallmarks of amyloid fibrils, in hopes of pursuing new therapeutic approaches for Alzheimer’s disease.
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While the research into amyloid β proteins has major implications for the medical community’s understanding of Alzheimer’s disease progression, it could also have broader implications for other amyloid-related diseases, like hereditary amyloidosis.
To study amyloid-β pathology, Scantox offers a variety of preclinical in vitro and in vivo models. In these models, amyloid-β pathology can be evaluated by several biochemical and histological approaches, including the A4-assay for the analysis of aggregated Aβ. Furthermore, several other typical Alzheimer’s disease-related pathologies, such as learning and memory deficits, neuroinflammation, increased neurofilament light chain levels as an indicator of neurodegeneration, and vascular pathology, can be evaluated.
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