Trigger for onset of Alzheimer's discovered
20 May 2013
The chemical changes in the brain that are at the root of
diseases such as Alzheimer’s have been mapped in detail for the
first time by scientists at the Chemistry Department of Cambridge
The breakthrough could lead to earlier diagnosis of
dementia-related diseases such as Alzheimer’s and Parkinson’s, and
opens up possibilities for a new generation of targeted drugs. In
2010, the Alzheimer’s Research Trust showed that dementia costs the
UK economy over £23 billion, more than cancer and heart disease
The study, published today in the journal PNAS, is a milestone in
the long-term research established in Cambridge by Professor
Christopher Dobson and his colleagues, following the realisation by
Dobson of the underlying nature of protein ‘misfolding’ and its
connection with disease over 15 years ago.
“There are no disease modifying therapies for Alzheimer’s and
dementia at the moment, only limited treatment for symptoms. We have
to solve what happens at the molecular level before we can progress
and have real impact,” said Dr Tuomas Knowles, lead author of the
study and long-time collaborator of Professor Dobson.
“We’ve now established the pathway that shows how the toxic
species that cause cell death, the oligomers, are formed. This is
the key pathway to detect, target and intervene — the molecular
catalyst that underlies the pathology.”
The neurodegenerative process giving rise to diseases such as
Alzheimer’s is triggered when the normal structures of protein
molecules within cells become corrupted.
Protein molecules are made in cellular ‘assembly lines’ that join
together chemical building blocks called amino acids in an order
encoded in our DNA. New proteins emerge as long, thin chains that
normally need to be folded into compact and intricate structures to
carry out their biological function.
Under some conditions, however, proteins can 'misfold' and snag
surrounding normal proteins, which then tangle and stick together in
clumps which build to masses, frequently millions, of malfunctioning
molecules that shape themselves into unwieldy protein tendrils.
The abnormal tendril structures, called ‘amyloid fibrils’, grow
outwards around the location where the focal point, or 'nucleation'
of these abnormal “species” occurs.
Amyloid fibrils, the type of protein structures
that are formed in Alzheimer’s, magnified a million times. Credit:
Dr Tuomas Knowles.
Amyloid fibrils can form the foundations of huge protein
deposits, called plaques, that have long been identified in the
brains of Alzheimer’s sufferers, and were once believed to be the
cause of the disease, before the discovery of ‘toxic oligomers’ by
Dobson and others a decade or so ago.
A plaque’s size and density renders it insoluble, and
consequently unable to move. Whereas the oligomers, which give rise
to Alzheimer's disease, are small enough to spread easily around the
brain, killing neurons and interacting harmfully with other
molecules, but how they were formed was until now a mystery.
The new work, in large part carried out by researcher Samuel
Cohen, shows that once a small but critical level of malfunctioning
protein ‘clumps’ have formed, a runaway chain reaction is triggered
that multiplies exponentially the number of these protein
composites, activating new focal points through ‘nucleation’.
It is this secondary nucleation process that forges juvenile
tendrils, initially consisting of clusters that contain just a few
protein molecules. Small and highly diffusible, these are the ‘toxic
oligomers’ that careen dangerously around the brain cells, killing
neurons and ultimately causing loss of memory and other symptoms of
The researchers brought together kinetic experiments with a
theoretical framework based on master equations, tools commonly used
in other areas of chemistry and physics but had not been exploited
to their full potential in the study of protein malfunction before.
The latest research follows hard on the heels of another ground
breaking study, published in April of this year again in PNAS, in
which the Cambridge group, in Collaboration with Colleagues in
London and at MIT, worked out the first atomic structure of one of
the damaging amyloid fibril protein tendrils. They say the years
spent developing research techniques are really paying off now, and
they are starting to solve “some of the key mysteries” of these
“We are essentially using a physical and chemical methods to
address a biomolecular problem, mapping out the networks of
processes and dominant mechanisms to ‘recreate the crime scene’ at
the molecular root of Alzheimer’s disease,” explained Knowles.
“Increasingly, using quantitative experimental tools and rigorous
theoretical analysis to understand complex biological processes are
leading to exciting and game-changing results. With a disease like
Alzheimer’s, you have to intervene in a highly specific manner to
prevent the formation of the toxic agents. Now we’ve found how the
oligomers are created, we know what process we need to turn off.”