Why memory-forming neurons are vulnerable to Alzheimer's
Date:
July 1, 2020
Source:
Rockefeller University
Summary:
Scientists have used advanced technology to 'micro-dissect' the
first brain cells to perish in Alzheimer's disease. The result is
a short list of genes that could represent new drug targets.
FULL STORY ==========================================================================
When Alzheimer's disease strikes, the entire brain doesn't crumble
at once.
Instead the mind unravels like grim clockwork, beginning with the telltale degradation of a group of brain cells in the entorhinal cortex. These
so-called vulnerable neurons are responsible for shuttling experiences
into memories.
They are always the first to go.
========================================================================== Figuring out why patients lose these vulnerable neurons early on could
be the key to discovering novel treatments for Alzheimer's. Now, a
new study sheds light on the inner workings of this subset of neurons
and describes the molecular factors that render entorhinal brain cells
uniquely sensitive to degeneration.
"If we can understand the peculiarities of the brain's most vulnerable
neurons, we can potentially open up new avenues for treatment," says Jean-Pierre Roussarie, senior research associate in the late Paul
Greengard's Laboratory of Molecular and Cellular Neuroscience, who
published the findings in Neuron.
"The smushy bowl of the brain" So far, attempts to develop a treatment
for Alzheimer's have largely failed.
But most efforts undertaken have centered on the accumulation of
A? peptides, which form plaques throughout the brain. These plaques are
the first sign of Alzheimer's, and the most studied.
The second sign of the disease is less celebrated, but may hold more
promise.
After the initial amyloid plaques form in the brain, a jumble of
tau proteins known as neurofibrillary tangles clog the insides of
neurons. Unlike amyloid plaques, this latter protein clump initially
clusters solely within a distinct group of cells of the entorhinal
cortex. The sheer predictability of the process makes it an attractive therapeutic target.
==========================================================================
But until now, scientists knew little about the nuances that make
vulnerable neurons tick and tangle. With that in mind, the researchers
set out to catalogue the genetic factors that render entorhinal neurons uniquely vulnerable to neurofibrillary tangles.
"There has been one trial after another, and we have accumulated a huge knowledge of the mechanisms that produce amyloid plaques," Roussarie
says. "But what is going on downstream of the amyloid accumulation,
and how these plaques trigger neurofibrillary tangles within vulnerable neurons, is much more of a puzzle. It is a place where we could discover
novel therapeutic targets." The biggest barrier to studying these brain
cells was the absence of any easy way to distinguish vulnerable neurons
from their neighbors. For Roussarie and his colleagues, BacTRAP provided
an answer. Developed at Rockefeller by Greengard and Nathaniel Heintz,
bacTRAP technology makes it possible to catalogue proteins within specific populations of neurons in mice.
"We needed something like a microdissection of these neurons from the
complex and smushy bowl of the brain," says Marc Flajolet, acting head
of the lab and coauthor on the study.
BacTRAP allowed the researchers to isolate the vulnerable neurons and
analyze how they differ, genetically, from more resilient brain cells. A Princeton University team led by Olga Troyanskaya then designed computer algorithms to help the team focus upon only the genetic anomalies likely
to be most relevant to neurodegeneration.
==========================================================================
"The goal was to form a big-picture view, rather than a list of genes," Flajolet says. "Only by way of these sophisticated data-analysis
frameworks can you get to the bottom of something as complicated as the neurodegenerative cascade in Alzheimer's disease." From neurofibrillary tangles to therapeutic targets The findings highlight a suite of genes
that are likely involved in making entorhinal cortex neurons easy targets
for degeneration.
The most compelling among them is thought to play a major role in the
early stages of Alzheimer's -- deciding whether tau proteins clump into neurofibrillary tangles in the first place. The gene produces a protein
called PTBP1, a so-called splice factor that directs cells to create
one of two subtypes of tau protein. Prior studies have shown that the characteristic protein clumps of Alzheimer's occur specifically when the
ratio of these two flavors of tau is disrupted -- and the new findings
suggest the disease might be driven by cells whose tau-variant levels
are disturbed.
"When tau popped out, there was a lot of excitement," says Vicky
Yao, an assistant professor in computer science at Rice University,
and co-author of the Neuron report. "Once we figure out what makes
neurons more vulnerable, that can lead to multiple avenues to decrease
their vulnerability." Successful strategies for preventing and
treating neurodegeneration will likely involve diverse approaches,
adds Roussarie. Future drugs may need to target plaque formulation as
well as neurofibrillary tangles, for example, and the first step toward preventing the latter will be to understand what makes some neurons
prone to tangling in the first place.
"The diversity of neurons was just not taken into account before,"
Roussarie says. "A lot of people are studying neurofibrillary tangles,
but only now are we beginning to address it through the prism of neuron vulnerability."
========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Jean-Pierre Roussarie, Vicky Yao, Patricia Rodriguez-Rodriguez, Rose
Oughtred, Jennifer Rust, Zakary Plautz, Shirin Kasturia, Christian
Albornoz, Wei Wang, Eric F. Schmidt, Ruth Dannenfelser, Alicja
Tadych, Lars Brichta, Alona Barnea-Cramer, Nathaniel Heintz,
Patrick R. Hof, Myriam Heiman, Kara Dolinski, Marc Flajolet, Olga
G. Troyanskaya, Paul Greengard. Selective Neuronal Vulnerability
in Alzheimer's Disease: A Network-Based Analysis. Neuron, 2020;
DOI: 10.1016/j.neuron.2020.06.010 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2020/07/200701125408.htm
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