New Study Reveals Molecular Structure of Alzheimer's Disease Brains

A landmark study has, for the first time, mapped the molecular structure of brains affected by Alzheimer's disease.

Researchers have created three-dimensional models of proteins within the brain, focusing in particular on beta-amyloid and tau, two proteins linked with Alzheimer's.

As work continues towards treatments for this neurodegenerative disease, building the fullest possible understanding of it remains essential.

Mapping Alzheimer's disease proteins in the brain

Protein clumps in the brain may either trigger Alzheimer's or result from it - scientists do not yet know which. A team at the University of Leeds in the UK has now provided an exceptionally detailed view of their arrangement, down to microscopic scale.

"This first glimpse of the structure of molecules inside the human brain offers further clues to what happens to proteins in Alzheimer's disease," says neuroscientist René Frank from the University of Leeds.

"But [it] also sets out an experimental approach that can be applied to better understand a broad range of other devastating neurological diseases."

The scientists examined post-mortem brain tissue from people with Alzheimer's using several advanced imaging methods. These included cryo-electron tomography (cryoET), which uses measurements from electron beams to produce three-dimensional maps of tissue held at extremely low temperatures.

Because cryoET can image tissue without chemical fixation or dehydration altering its biological structure, researchers can reconstruct three-dimensional tissue volumes at resolutions one million times smaller than a grain of rice.

"Light microscopic characterization of amyloid in Alzheimer's disease brain has formed the basis of diagnostic and disease classification," write the researchers in their published paper.

"The in situ structure of amyloid in the human brain is unknown."

What the 3D models revealed

By viewing these proteins so closely, researchers hope to gain a clearer picture of how the clumps develop and how they affect the brain.

Within beta-amyloid proteins, the team identified a combination of tiny thread-like formations known as fibrils and other structures. Tau proteins contained groups of filaments arranged in straight lines, though their layout appeared to differ according to their location in the brain.

Although the clusters resembled one another, their spatial organisation varied: tau filaments differed in their orientation and twisting, while beta-amyloid fibrils differed in size.

This is the first time these proteins have been examined at such a detailed level, and it is still too soon to establish the importance of the findings. With the method now proven, it can be applied to tissue from a broader selection of brain donors.

Extending the approach to neurodegenerative diseases

This should offer further insight into how these proteins appear at different stages of Alzheimer's progression. Comparing their structures over time may also show how the disease advances.

The team behind the study believes the method may help investigate the underlying causes of many neurodegenerative diseases, so further findings are likely to follow.

"Larger cohorts of diverse Alzheimer's disease donors, across different brain regions and at earlier stages of Alzheimer's disease, may reveal how the spatial organization of amyloid of different structures relates to individual neuropathological profiles," write the researchers.

"It will also be important to apply these approaches to other neurodegenerative diseases, many of which share related, or overlapping, types of amyloid neuropathology."

The research has been published in Nature.