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Illuminating the Structure of Amyloid Plaques

Scientists have long sought better understanding of the wide architectural variety of misfolded beta-amyloid plaque deposits in the brains of people with Alzheimer’s disease and how this multitude of amyloid shapes impacts the progression of dementia symptoms.

A team of researchers led by Dr. Mathias Jucker, at the German Center for Neurodegenerative Diseases in Tubingen, Germany used a new type of tissue sample staining dye – luminescent conjugated oligothiophenes (LCOs) -- to illuminate previously unseen structural forms of amyloid fibrils. Amyloid fibrils are aggregates of the peptide beta-amyloid that form plaques associated with neurological decline found in the brains of people with Alzheimer’s.

Using spectral analysis tools, scientists then used fluorescent light to track and mark the molecular and chemical composition of the LCOs, which, when bound to the beta-amyloid, reflected the 3D structure of the protein aggregates. The study revealed “clouds” of similar spectral signatures in brain samples from patients with distinct types of Alzheimer’s disease. Part of this work was supported through the Alzheimer’s Disease Centers program of the National Institute on Aging at NIH.

Jucker and his team analyzed donated postmortem brain tissue samples from people who had Alzheimer’s caused by family-carried genetic mutations, as well as other samples from typical and rare types of Alzheimer’s. They found that amyloid expressed unique spectral signatures in some, but not all, of these different types of the disease, such as slow-progressing versus fast-progressing. These amyloid spectral signatures varied within individual patients, but distinct areas of the brain showed similar average signatures.

Amyloid imaging from mouse brain samples; see caption
Researchers revealed the distinct architecture of different types of amyloid in mice using a unique class of luminescent dyes. Image courtesy of the National Academy of Sciences

The postmortem plaque samples were next injected into mice, whose brains were analyzed six months later. The unique amyloid structures seen in the human sample spectral analysis had mostly carried over to the mice, suggesting an underlying mechanism at the molecular level for the spread of distinct types of amyloid.

Next steps for the research team include using the new method to further explore mechanisms behind the different amyloid shapes in different types of Alzheimer’s, how they relate to severity of dementia symptoms, and how they might inform future potential targets for treatment.

Reference: Rasmussen J, Mahler J, Beschorner N, et al. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proc Natl Acad Sci USA. 2017 Dec 5;114(49):13018-13023