How gene expression changes in the brain in Alzheimer's disease

Date:
March 18, 2022
Source:
Universitat Autonoma de Barcelona
Summary:
An international group of researchers analyzed the genes that
are expressed in neurons and astrocytes based on data from 800
individuals and compared what happens in Alzheimer's patients
and in people without diagnosed dementia. The study highlights
the need to analyze molecular markers, such as genetic sequences
or brain proteins, to obtain more accurate assays, diagnoses
and therapies. The results also show changes in astrocytes in an
attempt to adapt to the toxic environment derived from the disease,
worsening its progression.



FULL STORY ==========================================================================
An international group of researchers led by the UAB analyzed the genes
that are expressed in neurons and astrocytes based on data from 800
individuals and compared what happens in Alzheimer's patients and in
people without diagnosed dementia. The study, published in Neurobiology
of disease, highlights the need to analyze molecular markers, such as
genetic sequences or brain proteins, to obtain more accurate assays,
diagnoses and therapies. The results also show changes in astrocytes in
an attempt to adapt to the toxic environment derived from the disease, worsening its progression.


========================================================================== Although Alzheimer's disease is one of the most studied pathologies due
to its high prevalence, the molecular changes that cause astrocytes,
a type of brain cell, to become reactive astrocytes, manifesting a very pronounced morphological change in response to a stressful situation,
are still unknown.

Neither is it known why neurons in diseased brains have difficulty communicating with each other or with the astrocytes themselves.

Now, in an article published in Neurobiology of Disease, an international
group of researchers with expertise in these cells and the study of neurodegenerative diseases analyzed genetic data from post-mortem brain
samples from nearly 800 individuals, to determine the differences between
gene expression in astrocytes and neurons from brains with the disease
and in cells from brains of people without a diagnosis of dementia,
the control group. The samples came from the Alzheimer Disease Knowledge
portal and were generated by three American clinics: Mount Sinai Hospital,
the Mayo Clinic and the Religious Order Study/ Memory and Aging Project.

Researchers studied the set of RNA molecules, or cellular transcriptome,
which is used to determine which of all the genes are being expressed and
to what extent. "By studying the transcriptome, we can see if there are silenced or overexpressed genes, and we can understand what is happening
inside neurons and astrocytes," explains Elena Galea, researcher at the Institut de Neurocie`ncies (INc-UAB) and first author of the article.

The results have shown a high genetic heterogeneity among people with the
same clinical diagnosis and, also, that more than half of the control individuals have a molecular profile of Alzheimer's disease, which is characterized by decreased expression of synaptic genes due to neuronal
damage and death. "This could indicate that these people were at a very
early stage of the disease (still without symptoms) and would reinforce
the idea that clinical diagnosis has to be complemented with the search
for molecular markers, such as neuronal synapse proteins, to determine
the phase in which the patient is," explains Lydia Gime'nez-Llort,
author of the article and researcher at the Department of Psychiatry
and Legal Medicine of the UAB and the INc-UAB. "In this sense, we are
working together with the Pasqual Maragall Foundation to detect astrocyte proteins in the blood of patients with preclinical Alzheimer's disease,"
adds Dr. Galea.

The study also shows how, as the disease progresses, astrocytes decrease
the expression of genes that code for mitochondrial proteins, which
prevents the mitochondria of these cells (basic organelles for cellular
energy) from functioning well. This effect could be an adaptation of
the astrocytes to compensate for the toxicity of the amyloid protein
and would be impairing communication between astrocytes and neurons. "We believe that this adaptation by astrocytes contributes to the worsening
of the disease and could therefore be a key point in preventing its progression," explains Dr. Galea.

The study is the most complete transcriptomic analysis of human astrocytes
in Alzheimer's disease to date and is of great relevance due to the number
of samples analyzed. The results highlight the need to use molecular
data to stratify patients into more genetically homogeneous groups for
clinical trials and to obtain a more accurate diagnosis and treatment of
the disease. Also, they open the door to developing targeted therapies
to protect the function of astrocyte mitochondria.


========================================================================== Story Source: Materials provided by
Universitat_Autonoma_de_Barcelona. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Elena Galea, Laura D. Weinstock, Raquel Larramona-Arcas, Alyssa
F. Pybus,
Lydia Gime'nez-Llort, Carole Escartin, Levi
B. Wood. Multi-transcriptomic analysis points to early organelle
dysfunction in human astrocytes in Alzheimer's disease. Neurobiology
of Disease, 2022; 166: 105655 DOI: 10.1016/j.nbd.2022.105655 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220318092118.htm

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