Mechanisms of neurotoxicity of amyloid aggregates
To find out more about this collaboration visit the Cambridge Bristol Toronoto Hamburg Neurodegenerative Disease Consortium website.
In the video below, Professor Peter St George-Hyslop explains how Alzheimer’s disease affects those with the condition and outlines the consortium’s strategy to uncover the molecular mechanisms by which accumulation of amyloid beta and/or tau leads to death of brain cells in AD and related neurodegenerative disorders (running time: 4 min 57 s).
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The problem
Alzheimer's disease and related disorders are increasingly common degenerative disorders of the brain that occur in mid-to-late adult life. They cause impairments in memory and intellectual function, and lead to death within 10-15 years of diagnosis.
In the UK, 700 000 people suffer from dementia (in around 450 000 of cases this is caused by Alzheimer's disease) and this number will double to 1.4 million by 2037. These diseases cost the UK economy about £17 billion, which will rise to at least £50bn by 2037.
Worldwide, 37m people are affected by these diseases - they are the fourth leading cause of death among adults in industrialised societies, and are becoming an increasingly significant healthcare problem in low- and middle-income countries.
Although we know that several genes and environmental effects can cause Alzheimer’s disease, we do not know why or how they lead to the death of nerve cells in the brain.
The paucity of knowledge about the molecular mechanics of these diseases has hampered the development of sensitive and accurate tests and effective treatments.
The questions
The accumulation and aggregation of two proteins in the brain - amyloid beta and tau - is a characteristic feature of Alzheimer's disease, while the accumulation of tau alone is characteristic of a related disorder called frontotemporal lobar degeneration-tau type. Mutations or variants in the amyloid precursor protein (APP), presenilin 1 (the enzyme that cuts APP and creates amyloid beta) or tau genes appear to play a crucial role in this process in some cases. This observation has led to the conclusion that events that cause the accumulation of amyloid beta and tau activate a set of downstream cellular signalling and metabolic events that ultimately kill nerve cells.
However, attempts using conventional tools to understand why brain cells are killed by the accumulation of these proteins have yielded confusing and conflicting results. We still do not know what types of aggregates formed by these proteins are toxic to brain cells, nor do we know how they disturb the metabolic and signalling machinery inside nerve cells.
Recently, the consortium has developed powerful biophysical and chemical approaches that will allow it to visualise individual aggregate species, to watch which types of aggregates bind to cells, and to identify the downstream pathways that they activate. Similarly, it has developed a variety of cellular and whole-organism models of these diseases as well as computational and systems biology tools that will allow understanding of how these toxic proteins affect the interlinked network of metabolic and signalling machinery inside nerve cells.
The research programme
The consortium will apply novel tools from physics, chemistry, computer science, genomics, biology and model organisms to generate a detailed understanding of the molecular mechanics that are activated by the accumulation of amyloid beta and tau, and that ultimately lead to the death of brain cells.
It aims to determine why and how both amyloid beta and tau accumulate in the brains of people with Alzheimer's disease, and why the normal mechanisms for removing aggregated proteins from brain cells become overwhelmed. It will also search for drug-like molecules that stabilise aggregation-prone proteins such as tau as potential therapies for these diseases.
The knowledge and tools generated will provide a rational basis for the future development of diagnostic profiles that could enable doctors to detect the disease in its earliest stages, before irreversible damage is done to the brain, and to personalise and monitor treatment programmes for individual patients, based on the cellular networks that have been disrupted.
Knowledge of these pathways will also provide potential targets for the development of new therapies to repair these pathways, thereby preventing or even reversing the disease.
The team
PRINCIPAL INVESTIGATOR
Cambridge Institute for Medical Research (CIMR), University of Cambridge
Peter St George-Hyslop
CO-INVESTIGATORS
University of Cambridge
Timothy Bussey (Dept of Experimental Psychology)
Damian Crowther (Dept of Genetics)
Christopher Dobson (Dept of Chemistry)
Giorgio Favrin (Dept of Chemistry)
Clemens Kaminski (Dept of Chemical Engineering and Biotechnology)
David Klenerman (Dept of Chemistry)
David Lomas (CIMR)
Cahir O’Kane (Dept of Genetics)
Stephen Oliver (Dept of Biochemistry)
David Rubinsztein (CIMR)
Lisa Saskida (Dept of Experimental Psychology)
Gergely Toth (Dept of Chemistry)
Michele Vendruscolo (Dept of Chemistry)
University of Bristol
Kei Cho
Graham Collingridge
Max-Planck-Unit for Structural Molecular Biology, Germany
Eckhard Mandelkow
Eva-Maria Mandelkow
University of Toronto, Canada
Paul Fraser
Ekaterina Rogaeva
Gerold Schmitt-Ulms
Image: Confocal image of an Alzheimer's-affected brain showing a region of amyloid plaque. Medical Microscopy Sciences, Cardiff University
