For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. Their results could have important implications for the development of potential treatments.
The international team, led by the University of
Cambridge, found that instead of starting from a single point in the brain and
initiating a chain reaction which leads to the death of brain cells,
Alzheimer’s disease reaches different regions of the brain early. How quickly
the disease kills cells in these regions, through the production of toxic
protein clusters, limits how quickly the disease progresses overall.
The researchers used post-mortem brain samples from
Alzheimer’s patients, as well as PET scans from living patients, who ranged
from those with mild cognitive impairment to those with full-blown Alzheimer’s
disease, to track the aggregation of tau, one of two key proteins implicated in
the condition.
In Alzheimer’s disease, tau and another protein called
amyloid-beta build up into tangles and plaques – known collectively as
aggregates – causing brain cells to die and the brain to shrink. This results
in memory loss, personality changes and difficulty carrying out daily
functions.
By combining five different datasets and applying them
to the same mathematical model, the researchers observed that the mechanism
controlling the rate of progression in Alzheimer’s disease is the replication
of aggregates in individual regions of the brain, and not the spread of
aggregates from one region to another.
The results, reported in the journal Science
Advances, open up new ways of understanding the progress of
Alzheimer’s and other neurodegenerative diseases, and new ways that future
treatments might be developed.
For many years, the processes within the brain which
result in Alzheimer’s disease have been described using terms like ‘cascade’
and ‘chain reaction’. It is a difficult disease to study, since it develops
over decades, and a definitive diagnosis can only be given after examining
samples of brain tissue after death.
For years, researchers have relied largely on animal
models to study the disease. Results from mice suggested that Alzheimer’s
disease spreads quickly, as the toxic protein clusters colonise different parts
of the brain.
“The thinking had been that Alzheimer’s develops in a
way that’s similar to many cancers: the aggregates form in one region and then
spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied
Department of Chemistry, the paper’s first author. “But instead, we found that
when Alzheimer’s starts there are already aggregates in multiple regions of the
brain, and so trying to stop the spread between regions will do little to slow
the disease.”
This is the first time that human data has been used
to track which processes control the development of Alzheimer’s disease over
time. It was made possible in part by the chemical kinetics approach developed
at Cambridge over the last decade which allows the processes of aggregation and
spread in the brain to be modelled, as well as advances in PET scanning and
improvements in the sensitivity of other brain measurements.
“This research shows the value of working with human
data instead of imperfect animal models,” said co-senior author Professor
Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see
the progress in this field – fifteen years ago, the basic molecular mechanisms
were determined for simple systems in a test tube by us and others; but now
we’re able to study this process at the molecular level in real patients, which
is an important step to one day developing treatments.”
The researchers found that the replication of tau
aggregates is surprisingly slow – taking up to five years. “Neurons are surprisingly
good at stopping aggregates from forming, but we need to find ways to make them
even better if we’re going to develop an effective treatment,” said co-senior
author Professor Sir David Klenerman, from the UK Dementia Research Institute
at the University of Cambridge. “It’s fascinating how biology has evolved to
stop the aggregation of proteins.”
The researchers say their methodology could be used to
help the development of treatments for Alzheimer’s disease, which affects an
estimated 44 million people worldwide, by targeting the most important
processes that occur when humans develop the disease. In addition, the
methodology could be applied to other neurodegenerative diseases, such as
Parkinson’s disease.
“The key discovery is that stopping the replication of
aggregates rather than their propagation is going to be more effective at the
stages of the disease that we studied,” said Knowles.
The researchers are now planning to look at the
earlier processes in the development of the disease, and extend the studies to
other diseases such as Frontal temporal dementia, traumatic brain injury and
progressive supranuclear palsy where tau aggregates are also formed during
disease.
Journal article: https://www.science.org/doi/10.1126/sciadv.abh1448
Source: Cause
of Alzheimer’s progression in the brain – Scents of Science (myfusimotors.com)
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