Clearance of protein linked to Alzheimer's controlled by circadian cycle
Ability of immune system to destroy Alzheimer's-related protein
oscillates with daily circadian rhythm
Date:
February 10, 2022
Source:
Rensselaer Polytechnic Institute
Summary:
The brain's ability to clear a protein closely linked to
Alzheimer's disease is tied to our circadian cycle, according to
new research. The research underscores the importance of healthy
sleep habits in preventing the protein Amyloid-Beta 42 (AB42)
from forming clumps in the brain, and opens a path to potential
Alzheimer's therapies.
FULL STORY ==========================================================================
The brain's ability to clear a protein closely linked to Alzheimer's
disease is tied to our circadian cycle, according to research published
today in PLOS Genetics. The research underscores the importance of healthy sleep habits in preventing the protein Amyloid-Beta 42 (AB42) from forming clumps in the brain, and opens a path to potential Alzheimer's therapies.
========================================================================== "Circadian regulation of immune cells plays a role in the intricate relationship between the circadian clock and Alzheimer's disease," said Jennifer Hurley, an expert in circadian rhythms, and associate professor
of biological science at Rensselaer Polytechnic Institute. "This tells
us a healthy sleep pattern might be important to alleviate some of
the symptoms in Alzheimer's disease, and this beneficial effect might
be imparted by an immune cell type called macrophages/microglia."
The research was conducted at the Rensselaer Center for Biotechnology
and Interdisciplinary Studies, which has a focus on neurodegenerative
disease. Dr.
Hurley worked with Rensselaer professors Robert Linhardt, a glycans
expert and inventor of synthetic heparin, and Chunyu Wang, whose ongoing research has detailed several mechanisms in the production and spread
of proteins implicated in Alzheimer's.
"This insight reveals a new mechanism and path to treatment of neurodegenerative diseases like Alzheimer's through an interdisciplinary approach, and is emblematic of the CBIS strength in research and discovery
and provides a new angle to human health and well-being," said Deepak Vashishth, director of the CBIS.
The circadian system is composed of a core set of clock proteins that anticipate the day/night cycle by causing daily oscillations in the levels
of enzymes and hormones, ultimately affecting physiological parameters
such as body temperature and the immune response. Disruption of the
circadian system is increasingly associated with diseases like diabetes, cancer, and Alzheimer's.
A telltale sign of Alzheimer's disease is plaques, extracellular clumps of
AB42 in the brain. Macrophages (referred to as microglia when they reside
in the brain), which are immune cells that seek and destroy unwanted
material, clear AB42 from the brain by ingesting it in a process called phagocytosis. In earlier research, Dr. Hurley and collaborators at the
Royal College of Surgeons in Ireland investigated circadian control
of macrophages, amassing an exhaustive dataset that made it possible
to see which macrophage RNA and proteins oscillate with a circadian
rhythm. The researchers noticed oscillations in enzymes that help to
make two proteins on the macrophage cell surface -- heparan sulfate proteoglycan and chondroitin sulfate proteoglycan- both of which are
known to play a role in regulating clearance of AB42.
Could these cell surface proteoglycans be a link between the circadian
system and Alzheimer's? In a series of elegant experiments testing
this hypothesis, the team established that the amount of AB42 ingested
by healthy macrophages oscillates with a daily circadian rhythm. That
pattern did not occur in macrophages without a circadian clock. They
also measured daily oscillations in the levels of heparan sulfate
proteoglycans and chondroitin sulfate proteoglycans produced on the
surface of macrophage cells with healthy circadian cycles. Peak AB42
clearance occurred as production of surface cell proteoglycans was at
its lowest level, and removal of these proteoglycans increased ingestion,
which suggests that the proteoglycans inhibit AB42 clearance.
"What's clear is that this is all timed by the circadian clock," said Dr.
Hurley. "When there's a lot of these cell surface proteoglycans, the macrophages don't ingest the AB42. We're not certain why that would be,
but there is definitely a relationship." That relationship could be
used to develop therapies that would encourage greater AB42 clearance,
perhaps by boosting the amplitude of daily oscillations, which tend to
diminish as we age.
"In theory, if we could boost that rhythm, perhaps we could increase
the clearance of AB42 and prevent damage to the brain," said Dr. Hurley.
At Rensselaer, Hurley, Linhardt, and Wang were joined in the research by Gretchen T. Clark, Yanlei Yu, Cooper A. Urban, Fuming Zhang, and Guo Fu,
who is now at the Chinese Academy of Sciences. "Circadian Control of
Heparan Sulfate Levels Times Phagocytosis of Amyloid Beta Aggregates"
was produced with support from the National Institutes of Health, the
National Science Foundation, and the Warren Alpert Foundation.
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
Rensselaer_Polytechnic_Institute. Original written by Mary
L. Martialay. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Gretchen T. Clark, Yanlei Yu, Cooper A. Urban, Guo Fu, Chunyu Wang,
Fuming Zhang, Robert J. Linhardt, Jennifer M. Hurley. Circadian
control of heparan sulfate levels times phagocytosis of amyloid
beta aggregates.
PLOS Genetics, 2022; 18 (2): e1009994 DOI:
10.1371/journal.pgen.1009994 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220210154215.htm
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