Microglia sense amyloid plaque hardness through Piezo1 to limit Alzheimer's disease progression Cell Press spoke to scientists

Life Sciences

Life science

Recently, Professor Mo Wei's team of Xiamen University published the research results entitled "Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer's disease" in the journal Neuron, revealing that microglia are activated by mechanical force receptor Piezo1 sensing fibrotic Aβ hardness and significantly improving AD-related pathological changes
.

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Alzheimer's disease (AD) is the most common neurodegenerative disease
in older people and is characterized by progressive cognitive impairment and behavioral impairment.
The two typical pathological features of AD are amyloid plaques in the brain, mainly formed by amyloid-β β (Aβ) fibrosis deposition, and nerve fiber tangles
caused by excessive phosphorylation of Tau protein in nerve cells.
At present, AD still lacks practical and effective treatment drugs, and with the extension of life expectancy and the aggravation of social aging, AD will be an urgent public medical problem
.

Microglia are resident innate immune cells of the central nervous system and play an important role
in maintaining brain homeostasis, brain development, and neurodegenerative pathology.
Studies have shown that many AD risk loci are unique to or highly expressed in microglia, suggesting that microglia are closely related to AD pathological changes and can even explore important potential AD therapeutic targets
.
Microglia can bind to chemical components such as Aβ in amyloid plaques through their surface receptors, triggering a microglial response to phagocytose and clear Aβ amyloid plaques
.
Although studies have shown that in vitro fibrosis Aβ has super hardness, it is not clear
how Aβ amyloid plaques in vivo change the hardness of the local brain tissue with which it is mounted.
Microglia have hardening properties (Durotaxis), but how microglia recognize the physical changes brought about by amyloid plaques, how to respond to activation, and how to ultimately affect the pathological process of AD are all questions that remain to be answered in the field of AD research
.

In this study, Methoxy-X04 was used to label Aβ amyloid plaques in the brain of AD mice and combined with atomic force microscopy to clarify for the first time that the mechanical hardness of Aβ amyloid plaque-related tissues in the brain slices of live AD mice was higher than that of non-Aβ amyloid plaques
.
In vitro utilizing a soft and hard hydrogel system, microglia are revealed by calcium imaging and cellular electrophysiological experiments to sense fibrotic Aβ hardness
through the mechanical force receptor Piezo1.
Further specific knockout of microglia Piezo1 aggravated the accumulation of Aβ in the brain of AD mice, cognitive behavior decline, and drug activation of microglia Piezo1 can alleviate AD-related phenotypes
.
This article reveals the protective role of microglia Piezo1-mediated signaling in the pathological process of AD from the perspective of mechanobiology, broadens the understanding that microglia are closely related to the pathological process of AD, and also provides a potential new target for the drug development of
AD.

The first author and co-corresponding author of the paper is Dr.
Hu Jin; PhD student Chen Qiang, master student Zhu Hongrui, and Hou Lichao, Department of Anesthesiology, Xiang'an Hospital affiliated to Xiamen University, are co-first authors
of this paper.
Professor Mo Wei and Professor Zhang Liang are the co-corresponding authors
of this paper.
Special thanks to Zhejiang University's National Health and Disease Human Brain Tissue Resource Bank for providing AD human brain tissue samples
for this study.
This research work has been supported by the National Key R&D Program, the National Natural Science Foundation of China Outstanding Youth Fund, the National Natural Science Foundation of China Youth Fund, and the General Fund
.

bright spot

• Aβ plaques increase the hardness of tissues

• Microglia sense fibrotic Aβ hardness through Piezo1, which is conducive to the clearance of Aβ in the brain of AD mice and reduces accumulation

• Microglial Piezo1 activation improves Aβ-related pathological changes

Author's interview

The public account of Cell Press specially invited Professor Mo Wei to accept an exclusive interview on behalf of the research team, asking him to further explain
it in detail.

CellPress：

How did you come up with the idea of linking microglia, mechanical force-sensing receptors, and Alzheimer's disease?

Professor Mo Wei:

In recent years, with the development and application of whole genome sequencing technology, many AD risk loci have been discovered, and interestingly, most of the AD-related risk genes are unique to or highly expressed in microglia, indicating that microglia are closely related
to AD pathological changes.
Microglia can bind to chemical components such as Aβ in amyloid plaques through their surface receptors, triggering a microglial response to phagocytosis to clear Aβ amyloid plaques
.
Studies have shown that in vitro fibrosis Aβ has super hardness, on the other hand, microglia have hardening characteristics
.
So we wondered whether fibrotic Aβ has this physical signal at work in triggering the microglial response, and the cell's perception of this hardness and so on mainly through mechanical force receptors, so we linked the three
.

CellPress：

We have always believed that the brains of Alzheimer's patients are softer than normal people, how can this be mentioned in your article that microglia perceive the hardness of patient tissues?

Professor Mo Wei:

Measurements of hardness in the brains of Alzheimer's patients did find that the brains were softer than normal brains due to the death of a large number of neurons and the accompanying demyelinating
.
Our findings were in local areas of the patient's brain, described in the text as adjacent to amyloid plaques, whose physical properties become more rigid due to changes in amyloid
plaques.

CellPress：

In addition to microglia, are other cells in the brain also likely to sense the hardness of amyloid plaques through Piezo1?

Professor Mo Wei:

After knocking out microglia Piezo1, we found that even activating Piezo1 with Yoda1 could not effectively reduce the accumulation of Aβ amyloid plaques in the brains of AD mice, indicating that microglial Piezo1 activation was the main reason why Yoda1 significantly reduced the accumulation of Aβ amyloid plaques in the
brains of AD mice.
Previous literature has reported that oligodendrocytes precursor cells, as well as astrocytes, also have Piezo1 expression
.
We do not rule out the possibility that other cells in the brain, such as Piezo1 expressed by astrocytes, will perceive the hardness of amyloid plaques, so the effect of Piezo1 on AD pathology in these cells needs to be further explored
.

CellPress：

Your article believes that Piezo1 plays a positive regulatory role in the process of microglia phagocytosizing Aβ amyloid plaques, how to explain the high expression of microglia Piezo1 around amyloid plaques, but finally can not effectively remove Aβ amyloid plaques?

Professor Mo Wei:

Yes, we found that Piezo1 expression was significantly increased in microglia around Aβ amyloid plaques, including in vitro soft and hard rubber experiments, and Piezo1 protein increased
in the presence of hardness stimulation.
The increase in this Piezo1 protein is likely to be the result
of a positive feedback stimulated by stiffness.
This suggests that with mechanical stimuli, Piezo1 can be activated and trigger downstream cellular functions, such as phagocytosis
.
Therefore, Piezo1 in microglia around amyloid plaques senses insoluble fibrotic Aβ hardness stimulation and exerts phagocytic function, but on the other hand, there are also articles reporting that soluble Aβ monomers or oligomers can inhibit Piezo1 activity
。 We know that amyloid plaques contain a large amount of soluble Aβ, so in the early stage, we think that Piezo1 is activated to engulf and limit amyloid plaques, but in the later stage, Piezo1 activity is inhibited by soluble Aβ, which may be a reason
why microglia around amyloid plaques can not effectively remove Aβ even if Piezo1 is highly expressed.
Treatment with the Piezo1 agonist Yoda1 in a mouse model of AD did also find that Piezo1 activation slowed the accumulation of
Aβ in the brain.

CellPress：

I see that you used the agonist Yoda1 of Piezo1 in mice in your article, do you think it is promising to be used clinically to relieve the symptoms of AD?

Professor Mo Wei:

At present, there are no fully effective drugs for the treatment of AD
.
From our current findings, Yoda1 still has some potential
.
Our study shows that Yoda1 can pass through the blood-brain barrier, and long-term subcutaneous administration of Yoda1 in mice did not cause obvious hepatotoxicity, while significantly slowing the accumulation of Aβ in the brain of AD mice and improving memory cognition
.
Of course, to be used as a therapeutic drug, we also need to do more and more detailed safety verification
.
In conclusion, our research provides new potential targets for drug discovery of AD
.

About the author

Mo Wei

professor

The corresponding author of the paper, Mo Wei, is a professor at the School of Life Sciences, Xiamen University, deputy director of the State Key Laboratory of Cell Stress Biology, a research group leader, a Minjiang scholar, a doctoral supervisor, and a recipient of
the National Outstanding Youth Fund 。 Mainly focusing on inflammatory stress caused by self and environmental changes, a series of innovative results with international impact have been achieved in recent years: the discovery of a new pathway for endogenous retroviral (ERV) transcript dsRNA to activate necrotizing apoptosis and host inflammation through the nucleic acid sensor ZBP1; Elucidating a novel mechanism of central nervous system inflammation caused by glial cell differentiation or migration disorders; It was reported that microglia in Alzheimer's disease sensed the physical hardness of Aβ amyloid plaque through the mechanical force receptor Piezo1, and activated the phagocytic function
of microglia to Aβ amyloid plaque.
In the past 5 years, the research results have been published in international mainstream academic journals such as Nature (2020), Molecular cell (2020), Advanced Science (2021), Nature Communications (2022), Neuron (2022) and other international mainstream academic journals
as corresponding authors.
At the same time, he serves as a standing committee member of the Cell Death Branch of the Chinese Society of Cell Biology and a member of the Gene Professional Branch of the Chinese Society of Biochemistry and Molecular Biology
.

Zhang Liang

associate professor

Co-corresponding author of the paper, Liang Zhang, doctoral supervisor, research group leader, associate professor
, School of Life Sciences, Xiamen University.
Mainly engaged in glial cells and white matter related research, explore the pathogenic mechanism of demyelinating-related diseases, and provide potential targets for the diagnosis and treatment of
brain diseases.
In recent years, the physiological functions and mechanisms of nucleoprein regulating nerve cell development and myelination by constructing transcriptional activation complexes around nuclear pores have been elucidated.
The autocrine regulatory mechanism of oligodendrocytes mediated by vesicles and the function of histone methylation modification in the regeneration of adult glial cells were discovered.
It was revealed that microglia sensed Aβ amyloid plaque hardness and thus limited the function of
Alzheimer's disease progression.
In the past 5 years, he has published papers
in international mainstream academic journals such as Neuron (2019), J Clin Invest (2022), Nat Commun (2022), Neuron (2022) and so on as a corresponding/co-corresponding author.
At the same time, he serves as a member of the Neural Regeneration and Repair Professional Committee of
the Chinese Research Hospital Association.

Hu Jin

doctor

The first author and co-corresponding author of the paper, Hu Jin, Ph.
D.
, an engineer at the School of Life Sciences, Xiamen University, mainly focuses on the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, and the research results are published in journals such as Neuron, Molecular Neurodegeneration, Neuropharmacology, PloS One and other journals
as the first or corresponding author (including co-)author.

CHEN Qiang

PhD candidate

Co-first author of the paper, Chen Qiang, a doctoral student at the School of Life Sciences, Xiamen University, under the tutelage of Professor Mo Wei, is currently engaged in the research
of metabolism and inflammation.

Zhu Hongrui

PhD candidate

Co-first author of the paper, Zhu Hongrui, a master's graduate of Xiamen University School of Medicine, is currently a doctoral candidate in anesthesiology at the First Affiliated Hospital of University of Science and Technology of China, engaged in research related to
severe brain protection.

Hou Lichao

professor

Co-first author of the paper, Hou Lichao, professor and doctoral supervisor of Xiamen University School of Medicine, director and chief physician of the Department of Anesthesiology of Xiang'an Hospital affiliated to Xiamen University, high-level talents introduced by Fujian Province, member of the Anesthesiology Teaching Guidance Subcommittee of Higher Education Institutions of the Ministry of Education, is clinically good at surgical anesthesia, first aid and resuscitation, intensive treatment, etc.
of various difficult and critical patients, and is well versed in the clinical manifestations and diagnosis and treatment status of sepsis; In terms of scientific research, he is mainly engaged in the research of sepsis and perioperative organ function protection, especially focusing on the research of immune inflammation mechanism and prevention strategies of central nervous system injury, responsible for and completed 3 National Natural Science Foundation projects, published 48 related articles, and the cumulative number of citations is 1631 (Neuron, 2022; Front Immunol.
, 2022; Molecular Neurobiology, 2022; Int J Neurosci.
, 2022; J Cell Mol Med.
, 2021; Int Immunopharmacol.
, 2020; Apoptosis.
, 2019; Shock.
, 2010; Shock.
, 2010; Shock.
, 2010; Shock.
, 2009 et al.
).

Relevant paper information

▌Papers:

Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease

▌Paper URL:

style="white-space: normal;box-sizing: border-box;" _msthash="251189" _msttexthash="10239255">▌ DOI：

https://doi.
org/10.
1016/j.
neuron.
2022.
10.
021

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