Investigators have identified structural differences between amyloid-beta (Abeta) aggregates in the postmortem brains of patients with inherited and sporadic Alzheimer's disease (AD), respectively. Moreover, both were different from the aggregates that form when Abeta assembles in vitro.

The authors wrote in their paper that their findings "may lead to the development of inhibitors of assembly and improved imaging agents."

The work, which was published in the January 14, 2022, issue of Science by researchers from Indiana University and the Medical Research Council Laboratory of Molecular Biology, is part of a larger effort to classify neurodegenerative diseases according to modern biological criteria, rather than symptom-based classifications that are centuries old and have been of no use as a basis for developing effective treatments.

Some of that effort has gone into classifying disease subtypes according to gene expression, while other scientists have looked at how brain diseases sort themselves at the neural circuit level.

The work published in Science used electron cryo-microscopy (cryo-EM) to peer at the atomic-level protein structure of Abeta42. Amyloid precursor protein can be cut into Abeta-peptides of different lengths. Abeta42 is the most common type of those peptides.

The team looked at 10 patients. Three of those patients had sporadic AD, 2 had familial AD, and 5 had other neurodegenerative conditions.

The Abeta plaques that are a core anatomical feature of AD are built up of different subunits. Individual Abeta peptides assemble into protofilaments, which assemble into filaments, which assemble into fibrils. Finally, fibrils aggregate into plaques.

The team identified two structurally related but distinct protofilament folds, which aggregated into two distinct types of filaments. Type I filaments were characteristic of sporadic AD, while type II filaments occurred in inherited AD and other neurodegenerative disorders.

Et tau, Brute?

Amyloids, though often thought of as synonymous with beta-amyloids, are not unique to either Abeta or AD. Scientifically speaking, the intracellular tau tangles that are the second protein calling card of AD are also filamentous amyloids.

In work published last fall in Nature, the team had used its structural approach to investigate tauopathies, a group of including AD that are characterized by aggregates of tau protein. They identified several new ways in which tau protein can misfold and aggregate, and linked them to specific mutations in the gene encoding tau, the microtubule-associated protein tau gene or MAPT.

In a commentary published along with the paper, researchers from the Swiss Federal Institute of Technology argued that the Nature study made a strong, if indirect, case that tau aggregation is a causal factor in tauopathies. "It is difficult to imagine a scenario in which the 19 different neurodegenerative tauopathy diseases analyzed so far lead to the misfolding of tau into reproducible fibrils in a total of 17 different ways," they wrote.

And in a critical insight of the work for drug discovery, the team showed that the method of choice to induce aggregation in vitro -- in the case of tau, this is done using heparin -- produced aggregates whose folding was unlike that seen in vitro.

Co-corresponding authors Sjors Scheres and Michel Goedert, both of the MRC, presented their work in a virtual seminar last year. Scheres said that the first step to developing inhibitors of the different aggregates was the development of a relevant in vitro system.

"Having a working in vitro system that we know replicates these structures will be important if you were to develop some molecules that inhibit filament growth," he said, recounting a meeting of his with a pharmaceutical company that was using heparin-aggregates tau in screening for inhibitors: "That probably is not the right way to go."