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Source—Liang Xiaoyan, editor—Wang Sizhen, Fang Yiyi, editor—Wang Sizhen
, a large amount of epidemiological evidence shows that aerobic exercise improves cognition and decreases An important lifestyle for the risk of developing Alzheimer's disease (AD) [1].
However, the molecular mechanism by which aerobic exercise protects cognitive function has not been fully elucidated
.
Blood-brain barrier (BBB) damage plays an important role in the development of AD pathology
。 Studies have found that changes
such as increased BBB permeability can occur in the early stages of AD.
As the disease progresses, the structural destruction and dysfunction of the BBB become more and more serious, which greatly reduces the clearance of β-amyloid (β Aβ) in the brain, and ultimately causes cognitive decline [2]
。 Aerobic exercise has been found to improve aging-related BBB function [3], but whether it can reduce AD The associated BBB injury and its corresponding molecular mechanisms are unknown
.
Actively exploring the intrinsic mechanism of aerobic exercise to improve AD-related B BB injury is expected to provide important guiding significance
for the prevention and treatment of AD.
On December 11, 2022, Du Yifeng, Department of Neurology, Affiliated Provincial Hospital of Shandong First Medical University The research group published a report entitled " Exosomal miR-532-5p induced by long-term exercise rescues blood–brain barrier function in 5XFAD mice via downregulation ofEPHA4"
。 Dr.
Xiaoyan Liang is the first author of the paper, and Professor Du Yifeng and Associate Professor Hou Tingting are the co-corresponding authors
of the paper.
In this study, the authors found that long-term aerobic exercise significantly increased the cross-blood-brain barrier clearance of Aβ in the brain, thereby improving the learning and memory ability
of 5XFAD mice.
This process is mediated by miR-532-5p in neuronal
exosomes.
The exosomes carrying miR-532-5p released by neurons can be taken up by blood-brain barrier endothelial cells and pericytes, thereby significantly improving the structure and function of the blood-brain barrier, ultimately increasing the clearance of Aβ in the brain and improving cognitive function
.
(Further reading: The relevant research progress of Du Yifeng's team, see the "Logical Neuroscience" report (click to read): Cereb Cortex-Du Yifeng/Qiu Chengxuan's research group reveals KIBRA.
) The complex relationship between gene polymorphisms and gray matter structure and olfactory function in the elderly brain) First,
the researchers used 5XFAD dementia model mice and littermate wild-type mice to establish a long-term aerobic exercise model to observe their learning and memory ability and brain in mice Effects of Aβ clearance across the blood-brain barrier
.
The study found that after long-term aerobic exercise, the learning and memory ability of 5XFAD mice was significantly improved
.
At the same time, the cross-blood-brain barrier clearance of Aβ in the brain of mice was also significantly enhanced (Figure 1).
The above results show that long-term aerobic exercise has a significant protective effect
on dementia-related cognitive impairment.
Figure 1Long-term aerobic exercise promotes β-amyloid clearance across the blood-brain barrier and improves cognition (Source: Liang, X.
et al.
, Aging Cell Smith et al.
, 2022)
to further verify whether enhanced Aβ clearance across the blood-brain barrier after long-term aerobic exercise benefits from improved blood-brain barrier structure and function[4] The researchers examined the structural and functional changes
of endothelial cells and pericytes, key components of the blood-brain barrier, by immunoblotting and staining.
The study found that after aerobic exercise, the expression of endothelial tight junction proteins ZO-1, Claudin 5 and pericyte functional proteins PDGFRβ and NG2 was significantly increased, while microvascular leakage in the brain of 5XFAD mice was also significantly reduced, and Aβ transported key receptors across the blood-brain barrier The expression of LRP1 in the whole brain of mice, as well as on endothelial cells and pericytes was also significantly increased (Figure 2).
The above results showed that aerobic exercise could significantly improve the blood of mice with dementiaBrain barrier structure and function
.
Figure 2: Long-term aerobic exercise improves blood-brain barrier structure and function (Source: Liang, X.
et al.
, Aging Cell, 2022)
Exosomes are important mediators
for cell-to-cell communication.
Several studies have shown that exosomes released during exercise can play a "paracrine" or "endocrine" role and are taken up by neighboring or distant cells, thereby transmitting bioactive molecules and affecting the function of target cells or organs [5].
Therefore, the researchers speculate whether long-term aerobic exercise can affect the structure and function
of BBB through exosomes as a medium.
In order to verify this, the researchers first extracted brain tissue exosomes from sports and non-exercise mice in vitro and verified the morphology and specific
proteins.
Then, primary endothelial cells and primary pericytes were co-cultured with mouse brain tissue exosomes, and it was found that exosomes could be taken up
by endothelial cells and pericytes.
At the same time, the brain tissue exosomes of exercise mice taken up by cells can significantly increase the expression of endothelial tight junction protein ZO-1 and pericyte functional proteins PDGFRβ and NG2, reduce apoptosis and improve cell survival (Figure 3).
。 These results show that long-term aerobic exercise can promote the production of functional exosomes, which act on BBB and exert a protective effect
.
Figure 3: Brain tissue exosomes of exercise mice exert BBB protection (Source: Liang, X.
et al.
, Aging Cell, 2022)
In order to clarify the functional molecules that play a protective role in exosomes in brain tissues of exercise mice, the researchers screened possible miRNAs and finally found that after exosomes in brain tissues of exercise mice were taken up by cells, Significantly increases intracellular miR-532-5p levels
.
In vitro and in vivo overexpression of miR-532-5p further confirmed that increasing the level of miR-532-5p could significantly improve endothelial tight junction protein ZO-1 and pericyte functional protein PDGFRβ and NG2 and Aβ clears the expression of receptor LRP1 across the BBB, reduces apoptosis of cells, improves cell survival, and alleviates the deposition of Aβ in the mouse brain (Figure 4
。 Therefore, miR-532-5p in exosomes may be a functional molecule in which motor exosomes play a protective role against BBB.
Figure 4: miR-532-5p in exosomes is a functional molecule that exercises BBB protection (Source: Liang, X.
et al.
).
Aging Cell, 2022)
Exercise can cause systemic changes
in the body.
To determine the histocellular source of exosomes carrying miR-532-5p, the researchers extracted total miRNA from kidney, liver, muscle, and brain tissue.
By comparing the changes of miR-532-5p in non-motor state and each tissue before and after exercise, it was found that the expression of miR-532-5p in brain tissues was the highest in the non-motor state, and the increase after exercise was the most significant.
Neurons and astrocytes are the most important cells of the nervous system, and the researchers used in situ hybridization double labeling experiments to further observe the expression changes of miR-532-5p in neurons and astrocytes before and after exercise, and found that miR-532-5p changes in neurons were the most significant ( Figure 5).
Therefore, the above results suggest that long-term aerobic exercise can promote information exchange
between neurons and B BB through exosome delivery of miR-532-5p.
Figure 5: Long-term aerobic exercise promotes communication between neurons and BBB through exosome delivery of miR-532-5p (Source: Liang, X.
et al.
, Aging Cell, 2022)
researchers used the database to further predict the downstream target gene of miR-532-5p
。 Diluciferase reporter experiments demonstrated that miR-532-5p binds to the 3' UTR region
of E PHA4.
EPHA4 is highly expressed in the brain tissue of AD mice, and previous studies have reported that it is associated with
blood-brain barrier damage in stroke.
After overexpression of miR-532-5p in this study, the expression of EphA4 protein in mouse brain tissue was significantly reduced
.
After cell silencing of the EPHA4 gene in vitro, the expression of endothelial tight junction protein and pericyte functional protein was significantly increased (Figure 6).
The above results suggest that miR-532-5p can be inhibited by EPHA4 expression plays a role
in improving B BB function.
Figure 5 miR-532-5p protects BBB by inhibiting EPHA4 expression (Source: Liang, X.
et al.
, Aging Cell, 2022)
Conclusion and discussion, inspiration and prospects
In summary, this study reveals that long-term aerobic exercise can act on the BBB by promoting neuronal exosome delivery miR-532-5p through a variety of experimental methods in vitro, thereby improving its structure and function, and ultimately enhancing the trans-BBB of Aβ Clearing, improve learning and memory ability
.
This study confirms the positive role of miR-532-5p in the pathogenesis and development of AD, suggesting that the recovery of BBB function may be a potential target for delaying AD progression The prevention and treatment of AD provides a possible entry point
.
In future research, it may be possible to further explore whether exosome miR-532-5p can accurately target specific brain regions or specific cell populations based on cell-to-cell information transmission, so as to develop a new set of precision treatment tools
that can be used for early treatment of AD.
Original link: http:// doi: 10.
1111/acel.
13748
This research was supported by the National Key Research and Development Program of China (2017YFC1310100), the National Natural Science Foundation of China (81861138008, 81772448, 82001120), and the Natural Science Foundation of Shandong Province (ZR2021MH392).
ZR2021QH240), Jinan Science and Technology Development Plan Project (202134028) and other projects
.
Corresponding author: Professor Du Yifeng
(Photo courtesy of Professor Du Yifeng's team).
。
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