summary: In a groundbreaking study, scientists have uncovered the molecular makeup of the brains of people with Alzheimer’s disease. Using cryo-electron tomography and fluorescence microscopy, the researchers created 3D maps of the proteins that cause dementia, including beta-amyloid and tau.
The study provides new insight into how these proteins disrupt communication between cells and cause the symptoms of Alzheimer’s, a discovery that could pave the way for new treatments for neurological disorders.
Key Facts:
- Innovative Imaging: Cryo-electron tomography and fluorescence microscopy used for protein mapping.
- Main proteins: We focus on beta-amyloid plaques and tau filaments, which are crucial in Alzheimer’s disease.
- Future treatments: This insight could lead to new therapeutic targets for Alzheimer’s and other neurological disorders.
sauce: University of Leeds
Scientists studying Alzheimer’s disease have, for the first time, uncovered the molecular structure of the disease in the human brain.
Released today NatureThe study describes how scientists used cryo-electron tomography with a fluorescence microscope to look deep inside the brains of donors with Alzheimer’s disease.
This resulted in a three-dimensional map that allowed researchers to see proteins, the molecular building blocks of life, inside the brain at a size one million times smaller than a grain of rice.
The study focused on two dementia-causing proteins: beta-amyloid, a protein that forms tiny, sticky plaques, and tau, a protein that in Alzheimer’s disease grows inside cells and forms abnormal filaments that spread throughout the brain.
This study revealed the molecular structure of tau in tissues, the arrangement of amyloid, and new molecular structures intertwined with this pathology in the brain.
Dementia is the leading cause of death in the UK, with Alzheimer’s disease being the most common.
In Alzheimer’s disease, both beta-amyloid plaques and abnormal tau filaments are thought to disrupt communication between cells, causing symptoms such as memory loss, confusion and cell death.
Lead author Dr René Frank, Associate Professor in the School of Biology at the University of Leeds, said: “This first glimpse into the molecular architecture inside the human brain not only provides further clues about what happens to proteins in Alzheimer’s disease, but also presents an experimental approach that can be applied to better understand a range of other devastating neurological disorders.”
Over the past 70 years, thousands of scientists around the world have studied proteins individually in test tubes, amassing vast catalogues of molecular structures, but we have long known that most functions in biology are the result of an orchestra of many different proteins.
The research, carried out by the University of Leeds in collaboration with scientists from Amsterdam University Medical Centre, Zeiss Microscopy and the University of Cambridge, is part of a new effort by structural biologists to study proteins directly within cells and tissues, in their native environment, to investigate how proteins work together and affect each other in human cells and tissues, particularly those ravaged by disease.
In the long term, observing protein interactions in tissues will hopefully accelerate the identification of new targets for the next generation of mechanism-based therapeutics and diagnostics.
About this Alzheimer’s research news
author: Leanne Dewsnap
sauce: University of Leeds
contact: Leanne Dewsnap – University of Leeds
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Cryo-ET of β-amyloid and tau in postmortem brains of Alzheimer’s diseaseRené Frank et al. Nature
Abstract
Cryo-ET of β-amyloid and tau in postmortem brains of Alzheimer’s disease
The defining pathological feature of most neurodegenerative diseases is the aggregation of proteins into amyloids, forming disease-specific structures.
Alzheimer’s disease is characterized by the deposition of disease-specific β-amyloid and tau deposits, but the in situ structure of amyloid in the human brain is unknown.
Here, we used targeted cryosectioning with cryofluorescence microscopy, lift-out with cryo-focused ion beam scanning electron microscopy, and cryo-electron tomography to determine the intratissue architecture of β-amyloid and tau pathology in the brains of postmortem Alzheimer’s disease donors. β-amyloid plaques contained some branched fibrils and a mixture of fibrils arranged in parallel arrays and lattice-like structures.
Extracellular vesicles and cuboidal particles defined the non-amyloid component of β-amyloid plaques. In contrast, tau inclusions formed parallel clusters of unbranched filaments.
Subtomograms averaging clusters of 136 tau filaments in a single tomogram revealed the polypeptide backbone structure and filament polarity orientation of paired helical filaments within the tissue. Filaments within most clusters were similar to each other but differed between clusters, indicating amyloid heterogeneity that was spatially organized by subcellular location.
The in situ construction approach on human donor tissue outlined here can be applied to a wide range of neurodegenerative diseases.
