Instability of brain activity during sleep and anesthesia underlies the pathobiology of Alzheimer's disease, study finds
Date:
February 1, 2022
Source:
Tel-Aviv University
Summary:
A new study revealed a pathological brain activity that
precedes the onset of Alzheimer's first symptoms by many years:
increased activity in the hippocampus during anesthesia and sleep,
resulting from failure in the mechanism that stabilizes the neural
network. The researchers believe that the discovery of this abnormal
activity during specific brain states may enable early diagnosis
of Alzheimer's, eventually leading to a more effective treatment
of a disease that still lacks effective therapies.
FULL STORY ==========================================================================
A new study at Tel Aviv University revealed a pathological brain activity
that precedes the onset of Alzheimer's first symptoms by many years:
increased activity in the hippocampus during anesthesia and sleep,
resulting from failure in the mechanism that stabilizes the neural
network. The researchers believe that the discovery of this abnormal
activity during specific brain states may enable early diagnosis of Alzheimer's, eventually leading to a more effective treatment of a
disease that still lacks effective therapies.
==========================================================================
The study was led by Prof. Inna Slutsky and doctoral students Daniel
Zarhin and Refaela Atsmon from the Sackler Faculty of Medicine and
the Sagol School of Neuroscience at Tel Aviv University. Additional participants in the study include: Dr. Antonella Ruggiero, Halit Baeloha,
Shiri Shoob, Oded Scharf, Leore Heim, Nadav Buchbinder, Ortal Shinikamin,
Dr. Ilana Shapira, Dr. Boaz Styr, and Dr. Gabriella Braun, all from
Prof. Slutsky's laboratory. Collaborations with the laboratory teams of
Prof. Yaniv Ziv of the Weizmann Institute, and Prof.
Yuval Nir of TAU were essential for the project. Prof. Tamar Geiger,
Dr. Michal Harel, and Dr. Anton Sheinin of Tel Aviv University, as well
as researchers from Japan, also contributed to the study. The article
was published in the scientific journal Cell Reports.
Prof. Slutsky: "According to the recent study published this month in
the Lancet Public Health journal, the number of people with dementia
worldwide will increase from 50m in 2019 to more than 150m in 2050,
growing by ~370% in North Africa and the Middle East. In Israel, a 145% increase is predicted, compared to ~74% in Western Europe. This huge
increase in the prevalence of Alzheimer's due to the expected rise
in population growth and in life expectancy will continue unless we
develop effective treatments. This is clearly an alert for investing in dementia research and its most frequent form -- Alzheimer's disease." "Innovative imaging technologies developed in recent years have revealed
that amyloid deposits, a hallmark of Alzheimer's disease pathology,
are formed in patients' brains as early as 10-20 years before the
onset of typical symptoms such as memory impairment and cognitive
decline. Unfortunately, most efforts to treat Alzheimer's disease by
reducing the amount of amyloid-beta proteins and their aggregation
have failed. If we could detect the disease at the pre- symptomatic
stage, and keep it in a dormant phase for many years, this would be
a tremendous achievement in the field. We believe that identifying a
signature of aberrant brain activity in the pre-symptomatic stage of Alzheimer's and understanding the mechanisms underlying its development
is a key to effective treatment." The researchers used animal models
for Alzheimer's, focusing on the hippocampal region of the brain,
which plays a key role in memory processes, and is known to be impaired
in Alzheimer's patients. At first, they measured cell activity in the hippocampus when the model animal was awake, active, and exploring its surroundings. For this they used advanced methods that measure brain
activity at a resolution of single neurons.
Daniel Zarhin: "Previous studies have examined cell activity in the
brains of anesthetized animals in a model for Alzheimer's and found overactivity in the hippocampus and cortex. To my surprise, when I
examined the model animals, I found no difference between the activity
of neurons and synapses in their hippocampus and corresponding activity
in the control group of healthy animals." In light of these findings,
the researchers decided to examine activity in the hippocampus in
other states of consciousness -- under anesthesia and during natural
sleep. Refaela Atsmon: "It is known that neuronal activity of the
hippocampus decreases during sleep in healthy animals. But when I
examined model animals in early stages of Alzheimer's, I found that
their hippocampal activity remained high even during sleep. This is due
to a failure in the physiological regulation, never before observed
in the context of Alzheimer's disease." Daniel Zarhin found similar dysregulation in model animals under anesthesia: neuronal activity does
not decline, the neurons operate in a manner that is too synchronized,
and a pathological electrical pattern is formed, similar to 'quiet'
seizures in epileptic patients. Halit Baeloha, who is researching sleep problems related to Alzheimer's disease, emphasizes that the discovered disruption begins before the onset of the typical sleep disturbances
observed in Alzheimer's patients.
========================================================================== Prof. Slutsky: "We found that brain states that block responses to the environment -- such as sleep and anesthesia -- expose abnormal activity
which remains hidden when the animal is awake, and this happens before
the symptoms of Alzheimer's disease are observed. Even though this
abnormal activity can be detected during sleep, it is much more frequent
under anesthesia. Therefore, it would be important to test whether
short anesthesia can be used for early diagnosis of Alzheimer's ."
At the next stage of the study, the researchers asked what causes the abnormality. To this end, they relied on findings from previous studies
from Prof. Slutsky's laboratory and other researchers on homeostasis
of neural networks: each neural circuit has a set point of activity,
maintained by numerous stabilizing mechanisms. These mechanisms are
activated when the balance is disturbed, restoring neuronal activity to
its original set point.
Is a disruption of these homeostatic mechanisms the main cause of aberrant brain activity during sleep and anesthesia in Alzheimer's disease animal models? To test this, Dr. Antonella Ruggiero examined the effect of
various anesthetics on neurons grown on a chip and found that they
lower the set point of neuronal activity. In healthy neural networks,
activity remained low over time, but in neural networks expressing
familial Alzheimer's mutations, the lowered set point recovers quickly,
despite the presence of anesthetics. In another experiment, Dr. Ruggiero increased neuronal activity, and once again she found a failure in the mechanisms responsible for restoring activity to its normal set point
in neurons expressing Alzheimer's mutations.
The researchers now sought to examine a potential drug for the impaired regulatory mechanism. Prof. Slutsky: "The instability in neuronal activity which we found in this study is known from epilepsy. In a previous study
we discovered that an existing drug for multiple sclerosis may help
epilepsy patients by activating a homeostatic mechanism that lowers the
set point of neural activity. Doctoral student Shiri Shoob examined
the effect of the drug on hippocampal activity in the animal model
for Alzheimer's and found that in this case also the drug stabilizes
activity and reduces pathological activity observed during anesthesia."
Prof. Slutsky concludes: "The results of our study may help early
diagnosis of Alzheimer's, and even provide a solution for instability
of neuronal activity in Alzheimer's disease. Firstly, we discovered
that anesthesia and sleep states expose pathological brain activity in
the early stages of Alzheimer's disease, before the onset of cognitive
decline. We also proposed the cause of the pathological activity --
failure of a very basic homeostatic mechanism that stabilizes electrical activity in brain circuits. Lastly, we showed that a known medication
for multiple sclerosis suppresses this type of anesthesia- induced
aberrant brain activity." The researchers now plan to collaborate with
medical centers in Israel and worldwide to test whether the mechanisms discovered in animal models can also be identified in patients with
early-stage Alzheimer's disease. For this purpose, they propose to
incorporate EEG monitoring into surgical procedures, to measure brain
activity of patients under anesthesia. They hope that their findings
will promote early diagnosis and drug development for the most common
form of late-onset dementia.
special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Tel-Aviv_University. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Daniel Zarhin, Refaela Atsmon, Antonella Ruggiero, Halit Baeloha,
Shiri
Shoob, Oded Scharf, Leore R. Heim, Nadav Buchbinder, Ortal
Shinikamin, Ilana Shapira, Boaz Styr, Gabriella Braun, Michal Harel,
Anton Sheinin, Nitzan Geva, Yaniv Sela, Takashi Saito, Takaomi
Saido, Tamar Geiger, Yuval Nir, Yaniv Ziv, Inna Slutsky. Disrupted
neural correlates of anesthesia and sleep reveal early circuit
dysfunctions in Alzheimer models. Cell Reports, 2022; 38 (3):
110268 DOI: 10.1016/ j.celrep.2021.110268 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220201115157.htm
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