Cause of Alzheimer's progression in the brain

Date:
October 29, 2021
Source:
University of Cambridge
Summary:
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.



FULL STORY ==========================================================================
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.

The study is a collaboration between researchers at the UK Dementia
Research Institute at the University of Cambridge, University of Cambridge
and Harvard Medical School. Funding is acknowledged from the Sidney
Sussex College Cambridge, the European Research Council Grant Number,
the Royal Society, JPB foundation, the Rainwater foundation, the NIH
and the NIHR Cambridge Biomedical Research Centre which supports the
Cambridge Brain Bank.

========================================================================== Story Source: Materials provided by University_of_Cambridge. The original
text of this story is licensed under a Creative_Commons_License. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Georg Meisl, Eric Hidari, Kieren Allinson, Timothy Rittman, Sarah L.

DeVos, Justin S. Sanchez, Catherine K. Xu, Karen E. Duff, Keith A.

Johnson, James B. Rowe, Bradley T. Hyman, Tuomas P. J. Knowles,
David Klenerman. In vivo rate-determining steps of tau seed
accumulation in Alzheimer's disease. Science Advances, 2021; 7
(44) DOI: 10.1126/ sciadv.abh1448 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211029152240.htm

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