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The peptide -
a small protein - beta-amyloid is strongly associated with Alzheimer's disease;
however, researchers are still looking for unequivocal proof that this peptide
is the causal agent of the onset and development of the disease. The main
obstacle impeding such confirmation is that beta-amyloid is not harmful when
found in isolation but only when it aggregates, that is when it self-assembles to
form the so-called amyloid fibrils
"We are
not dealing with a single target, beta-amyloid alone, but with multiple ones
because each aggregate of peptide, which can go from two units to 3,000 is a
potential target. Determining the aggregate responsible for neuronal death is
extremely complex and is one of the key issues for confirming or rejecting the
hypothesis regarding beta-amyloid," explains Natàlia Carulla, scientist at
the Institute for Research in Biomedicine (IRB Barcelona) and principal investigator
of the study published in the scientific journal ACS Chemical Biology.
In their latest work, Carulla and collaborators describe a technique that has
allowed them, for the first time, to distinguish different types of
beta-amyloid aggregates formed during aggregation and in parallel to establish
which is most toxic. The study provides further evidence in support of the
hypothesis that neuronal death is caused by intermediate aggregates of
beta-amyloid and reveals that the development of structure within these
aggregates determines their ability to cause neuronal death.
The Harmful
Forms of Beta-Amyloid
The study
shows that the most toxic aggregates are those formed by 20 to 100 units of
beta-amyloid, known as intermediate aggregates or precursor aggregates of
beta-amyloid fibrils. In contrast, the smaller aggregates of beta-amyloid and
the amyloid fibrils, which can contain up to 3,000 units of the peptide, do not
cause neuronal death.
The
scientists treated cultures of mouse neurons with samples obtained at different
times of the aggregation process. The point at which they observed the highest
neuronal death, reaching about 60%, occurred when cells were exposed to
intermediate aggregates of beta-amyloid that had developed a certain degree of
structure. The experiments with mouse neurons were performed in collaboration
with Eduardo Soriano's team at the University of Barcelona, they prepared
neuronal cultures from the hippocampus, the brain region in which neuronal lost
is first observed in Alzheimer's disease.
"The
technique that we have set up allows us to detect how the structure within
these aggregates increases, that is to say, how the aggregates take shape and
how they get organized. We observed that maximum toxicity occurs when they have
acquired a given degree of structure, a certain rigid part in the
aggregate," explains Carulla.
The
scientists uphold that this is precisely one of the most promising results of
the study. "We can see structure, organization and common pattern and
therefore the hope is that if we manage to characterize this pattern, we will
be able to look for and design therapeutic molecules that prevent their
formation or cause their disruption" says first author of the article
Bernat Serra-Vidal, whose PhD thesis was based on this work.
Furthermore,
the researchers explain that the tools developed to
study
beta-amyloid aggregation could be used to examine the aggregation of other
proteins that are associated with conditions such as Parkinson's disease, Huntington's disease, and type 2 diabetes.
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