Scientists investigating Alzheimer’s disease have determined the structure of molecules within a human brain for the very first time. Using cryo-electron tomography, guided by fluorescence microscopy, scientists say they explored deep inside an Alzheimer’s disease donor brain. The findings revealed the molecular structure of tau in tissue, how amyloids are arranged, and new molecular structures entangled within this pathology in the brain.
The findings are published in Nature in an article titled, “CryoET of β-amyloid and tau within post-mortem Alzheimer’s disease brain,” and led by scientists at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge.
“A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures,” the scientists wrote. “In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain.”
The study zoomed in on two proteins that cause dementia—”β-amyloid,” a protein that forms microscopic sticky plaques, and “tau”—another protein that in Alzheimer’s disease forms abnormal filaments that grow inside cells and spread throughout the brain.
Rene Frank, PhD, lead author and associate professor in the University of Leeds’s School of Biology, said: “This first glimpse of the structure of molecules inside the human brain offers further clues to what happens to proteins in Alzheimer’s disease but also sets out an experimental approach that can be applied to better understand a broad range of other devastating neurological diseases.”
This study carried out at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge, is part of new efforts by structural biologists to study proteins directly within cells and tissues, their native environment—and how proteins work together and affect one another, particularly in human cells and tissues ravaged by disease. In the longer term, it is hoped that observing this interplay of proteins within tissues will accelerate the identification of new targets for next-generation mechanism-based therapeutics and diagnostics.
