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How Does Amyloid Formation Impact Neurodegenerative Disease?

How Does Amyloid Formation Impact Neurodegenerative Disease?

What is Amyloid Formation?

An amyloid is a fibrous material made from protein.

A protein is a chain of amino acids and, unlike other polymers, the way this chain is arranged in 3D is often unique. The building blocks of protein structures, which are often referred to as a protein’s secondary structure, are mostly alpha-helical, where this chain of amino acids forms helices, or beta-sheets, where these chains form extended strands that stack to form sheet-like structures. In an amyloid, the protein chains form almost exclusively beta-sheets and they stack to form immensely long fibrillar structures.

How is Amyloid Formation Significant?

Amyloids are extremely strong structures, the properties of some of these materials rival steel in terms of their tensile strength (e.g. spider silk) and form the basis of some of the toughest natural glues, such as those allowing sea molluscs to stick to rocks. When these structures form in an uncontrolled way in the wrong biological compartment, they can lead to pathology.

How Was it Linked to Degenerative Diseases?

In degenerative disease and, in particular, in neurodegenerative conditions, the formation of amyloids in the brain seems to entail stable soluble intermediate structures that are toxic to our neurons. One of the first people to link the observation of amyloid plaques and tangles with a neurodegenerative condition was Alois Alzheimer in 1901. Since then, advances in protein science, genetics and cell biology have allowed us to dig deeper and understand where these come from and how they may lead to neuronal cell death.

Why is the Research into Amyloid Formation Particularly Challenging?

Amyloids emerge from natural proteins that are either structure-less or lose their original structures before assembling into an amyloid structure. Each amyloid fibril is made from thousands of highly dynamic protein chains that have so many possible orientations and populate so many different intermediately sized forms that standard structural biology techniques struggle to pin these down. As these intermediate structures are key to the toxic nature of this substance, we need to understand more about these. The literature refers to these molecular species as “oligomers”.

What are You Hoping to Find from Your Research?

In our work, we use pure samples of amyloid beta peptide, a protein that is causative in Alzheimer’s disease and observed how its spontaneous assembly into amyloid in the test tube. We have tested the impact of many different experimental set-ups and found conditions where the assembly occurs in a reliable and consistent manner. This has allowed us to begin to evaluate the ability of different drugs and biological molecules to prevent amyloid formation and even break it down. We can measure the amount of amyloid forming as a function of time but until recently, we have lacked a sensitive way to measure the “oligomers” and characterise their diversity.

How Does Field Flow Fractionation Help You Achieve this?

Asymmetric flow field flow fractionation, or AF4, provides a fantastic method for characterising the different species that arise during the assembly and indeed disassembly of amyloids. Standard fractionation methods that are generally applied to biological molecules are often too limited by the range of molecular weights they can contend with (amyloids are microns long) and by the use of solid surfaces that amyloids tend to stick to. AF4 is a liquid based fractionation method that can separate particles over a huge range, from the very small (sub – nanometres or < 10-9 m) to the very large (microns or 10-6 m). In the same run, we are able to quantify the amounts of different species over this whole range and estimate their molecular properties. When combined with visual techniques like electron or atomic force microscopy, this ability to quantify the material is a huge advance.

How has the AF2000 Helped You Achieve Better Results?

So far, we have used the technology to provide some very much needed quality control in our samples and ensure reliability of our experimental set-up. The sensitivity of amyloid forming material to the environment is notorious and the AF4 has allowed us to establish clear protocols to ensure reproducibility and a stronger interpretation of the data. This will form the first of our publications on this material. We have also begun to measure the formation of oligomers in different conditions and will observe the impact of proposed therapeutic drugs such as G3P protein on amyloids. This is within the framework of our BBSRC (research council) funded grant.

Where Do You See Your Research Going Within Degenerative Diseases?

We will be able to correlate the population of specific oligomers with observables such as toxicity to neurons, and more specifically binding to specific cellular receptors or impact on neuronal cell membranes. The ability of different drugs to impact on these processes will then be able to be characterised.

Where can Our Readers Find Out More About Your Research and the AF2000?

More information can be found on the following webpage: https://www.sheffield.ac.uk/mbb/staff/rosiestaniforth/rosiestaniforth.

 

About Dr Rosie Staniforth

Dr Rosie Staniforth trained as a protein chemist in the field of protein folding and developed one of the first mechanistic descriptions of the GroEL chaperone activity. In 1998, she came to the University of Sheffield (UoS) to train in structural biology and, in particular NMR spectroscopy, working on protein misfolding. Here, she was awarded a Wellcome Trust Career development fellowship and a Royal Society University Research Fellowship, the latter to address the mechanisms of formation of amyloid aggregates.

The model systems on which she has focussed primarily are cystatins, a family of cysteine protease inhibitors including members that cause a hereditary form of cerebral amyloid angiopathy (CAA). In CAA, cystatin C amyloid deposits in brain arteries leading to recurrent stroke and early death. Cystatins also play a role in the sporadic disease, which affects >50% of individuals in their 80s, including 90% of patients with Alzheimer’s disease (AD).

Cystatin C is listed as a strong candidate for a susceptibility gene for late-onset AD. Current work in her group focuses on the molecular details of this role and how it interacts with amyloid β peptide in both CAA and AD. This expertise is now being widened to understanding how natural compounds, both proteins and small molecules, bind to and regulate amyloidogenic proteins at different stages of assembly. Dr Staniforth is currently principal investigator on a BBSRC grant which investigates the molecular basis for the amyloid re-modelling activity of the protein G3P.

 

 

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