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Editor-in-Chief | Alzheimer's disease (AD) is a degenerative neurological disease of unknown origin
.
Clinically, it is mainly characterized by advanced brain function impairment such as progressive memory impairment and cognitive decline
.
The pathogenesis of AD is not yet fully understood, and there is a lack of effective treatments
.
Clinical imaging evidence shows that the brain of AD patients has obvious white matter changes [1,2], and the white matter of the brain contains a large number of myelinated nerve fibers
.
The myelin sheath (myelin) of the central nervous system (CNS) is formed by the protuberances of oligodendrocytes (OL) repeatedly surrounding the axons.
It has insulating axons, which can accelerate the conduction of nerve impulses and provide for the axons.
Nutritional support and other functions
.
The myelin sheath of the CNS of adult animals keeps dynamic changes.
On the one hand, there are a large number of oligodendrocyte precursor cells (OPCs) in the CNS, which can differentiate into OL to form new myelin; on the other hand, the formed myelin can be Slight degradation
.
Recent studies and previous work of the team have shown that the myelination of adult mice is closely related to the ability of spatial learning and memory, and the decrease of myelination is one of the important reasons for the decline of aging-related memory function [3-5]
.
Studies have found that the total amount of myelin in the AD brain is reduced, but the dynamic changes of myelin and its functional significance are still unclear
.
The team of Professor Mei Feng from the School of Basic Medical Sciences of the Army Military Medical University (Third Military Medical University) has been studying the dynamic changes of myelin sheath, its role and regulation mechanism in CNS development and diseases for a long time
.
On June 8, 2021, a research paper entitled "Enhancing myelin reverses cognitive dysfunction in a murine model of Alzheimer's disease" was published online in Neuron
.
This paper uses cell-specific fluorescent reporter transgenic mice to observe the newly formed myelin sheath and track the formed myelin in the APP/PS1 (AD model) mouse brain, revealing the unique dynamic changes of the myelin sheath in the brain of AD mice; Conditional knock-out mice, behavioral, electrophysiological recording and other methods have proved that the promotion of myelin renewal alleviates the decreased memory ability and hippocampal electrophysiological abnormalities in AD mice
.
This paper provides new laboratory evidence for understanding the changes and function of myelin sheath in the pathogenesis of AD (Figure 1)
.
Figure 1: Summary of main results.
Both existing studies and this paper have found that AD human brain specimens and AD model mouse brains have a wide reduction in total myelin sheath, and AD model mouse myelin sheath reduction occurs similarly to the decline in learning and memory ability.
(7 months old)
.
It is generally believed that the OPC differentiation disorder and abnormal myelination of the AD brain are one of the main reasons for the decrease of the total amount of myelin
.
In this paper, the researchers constructed APP/PS1; NG2-CreERT; Tau-mGFP fluorescent reporter mice to mark and observe the newborn myelin sheath, which was induced at the initial stage of memory decline (7 months of age) in APP/PS1 mice
.
Three months later, compared with controls of the same age, it was unexpectedly found that more new myelin sheaths appeared in the hippocampus, cortex, and corpus callosum of the brains of AD mice
.
It indicates that the remyelination of the brain of AD mice may be compensated by extensive demyelination, which is similar to the myelin repair process of other demyelinating diseases (such as multiple sclerosis)
.
In order to clarify the degradation of the formed myelin sheath and whether the newly formed myelin sheath can accumulate, the researchers constructed APP/PS1; PLP-CreERT; mT/mG fluorescent reporter mice
.
Myelin sheath (GFP+) was formed by the induction marker at the age of 2-4 months, and the material was taken at 13 months old, combined with MBP staining, it was observed that the myelin sheath (GFP+/MBP+, marked in blue) in the brains of AD mice was greatly reduced compared with the control group , But at the same time there is more newly formed myelin (GFP-/MBP+, marked in red) (Figure 2), indicating that the new myelin in the brain of AD mice can accumulate and increase
.
The above results suggest that although the new myelin sheath can accumulate and increase in the brain of AD mice, the rapid degeneration of the myelin sheath has formed, resulting in a decrease in the total amount of myelin sheath
.
Figure 2.
The accumulation of new myelin in the brain of APP/PS1 mice.
Because there is no effective method to prevent myelin degeneration, the researchers imagine that by enhancing the formation of endogenous myelin, it is possible to better repair the myelin, and Improve AD-related learning and memory decline
.
The research team confirmed in previous studies that the muscarinic receptor 1 (M1R) negatively regulates OPC differentiation and myelination, and promotes myelination in both developing and aging brains [5, 6]
.
Therefore, the researchers constructed APP/PS1; NG2-CreERT; M1R fl/fl; Tau-mGFP mice to promote the myelination of AD mice by inducing the expression of M1R knocked out of OPC
.
The M1R in the OPC of APP/PS1 mice aged 7-8 months was induced to knock out, and the results showed that the new myelin sheath in the mouse brain increased significantly after 3 and 6 months compared with the control group, and the total amount of myelin was recovered significantly
.
It is worth noting that the new myelin sheath increased linearly and continuously in March, June and September after induction of APP/PS1;M1R cKO mice
.
The above research results show that promoting myelination can effectively improve AD-related myelin degeneration
.
The researchers used the Morris water maze and new object recognition methods to further prove that promoting myelin renewal can significantly improve the cognitive dysfunction of APP/PS1 mice
.
Using methods such as in vivo recording, it has also been found that after increased myelination in M1R knockout mice, it can enhance memory-related neuron activation and the hippocampal sharp wave ripple (SWR) activity during slow-wave sleep
.
The treatment of APP/PS1 mice with the pro-myelination drug-clemastine also has a similar protective effect
.
In summary, this paper reveals the dynamic changes of AD-related myelin sheath, and proposes a treatment strategy to promote myelination to alleviate AD-related cognitive dysfunction
.
The first author of this article is Chen Jingfei, a 2018 PhD student in Histology and Embryology at the Army Military Medical University, Liu Kun, a 2018 master student in Developmental Biology, and Professor Hu Bo from the Department of Physiology; Professor Jonah R.
Chan, University of California, San Francisco, Army Professor Lan Xiao and Professor Feng Mei (lead contact) of the Military Medical University are the corresponding authors of this article
.
Figure 6.
Creative diagram of AD and myelin sheath (by Luo Yan) Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
05.
012 Reprint instructions [Non-original article] The copyright of this article belongs to the author of the article, and individuals are welcome Reposting and sharing, reprinting without permission is prohibited, the author has all legal rights, offenders must be investigated
.
References [1]BRUN A, ENGLUND E.
A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study [J].
Ann Neurol, 1986, 19(3): 253-62.
doi:10.
1002/ana.
410190306 [2]MIGLIACCIO R, AGOSTA F, POSSIN KL, et al.
White matter atrophy in Alzheimer's disease variants [J].
Alzheimers Dement, 2012, 8(5 Suppl): S78-87.
e1-2.
doi:10.
1016/j .
jalz.
2012.
04.
010[3]STEADMAN PE, XIA F, AHMED M, et al.
Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice [J].
Neuron, 2020, 105(1): 150-64.
e6.
doi :10.
1016/j.
neuron.
2019.
10.
013[4]PAN S, MAYORAL SR, CHOI HS, et al.
Preservation of a remote fear memory requires new myelin formation [J].
Nat Neurosci, 2020, 23(4): 487 -99.
doi:10.
1038/s41593-019-0582-1[5]WANG F, REN SY, CHEN JF, et al.
Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory [J].
Nat Neurosci, 2020, 23(4): 481-6.
doi:10.
1038/s41593-020-0588-8[6]WANG F, YANG YJ, YANG N, et al.
Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia [J].
Neuron, 2018, 99(4): 689-701.
e5.
doi:10.
1016/j.
neuron.
2018.
07.
017
.
Clinically, it is mainly characterized by advanced brain function impairment such as progressive memory impairment and cognitive decline
.
The pathogenesis of AD is not yet fully understood, and there is a lack of effective treatments
.
Clinical imaging evidence shows that the brain of AD patients has obvious white matter changes [1,2], and the white matter of the brain contains a large number of myelinated nerve fibers
.
The myelin sheath (myelin) of the central nervous system (CNS) is formed by the protuberances of oligodendrocytes (OL) repeatedly surrounding the axons.
It has insulating axons, which can accelerate the conduction of nerve impulses and provide for the axons.
Nutritional support and other functions
.
The myelin sheath of the CNS of adult animals keeps dynamic changes.
On the one hand, there are a large number of oligodendrocyte precursor cells (OPCs) in the CNS, which can differentiate into OL to form new myelin; on the other hand, the formed myelin can be Slight degradation
.
Recent studies and previous work of the team have shown that the myelination of adult mice is closely related to the ability of spatial learning and memory, and the decrease of myelination is one of the important reasons for the decline of aging-related memory function [3-5]
.
Studies have found that the total amount of myelin in the AD brain is reduced, but the dynamic changes of myelin and its functional significance are still unclear
.
The team of Professor Mei Feng from the School of Basic Medical Sciences of the Army Military Medical University (Third Military Medical University) has been studying the dynamic changes of myelin sheath, its role and regulation mechanism in CNS development and diseases for a long time
.
On June 8, 2021, a research paper entitled "Enhancing myelin reverses cognitive dysfunction in a murine model of Alzheimer's disease" was published online in Neuron
.
This paper uses cell-specific fluorescent reporter transgenic mice to observe the newly formed myelin sheath and track the formed myelin in the APP/PS1 (AD model) mouse brain, revealing the unique dynamic changes of the myelin sheath in the brain of AD mice; Conditional knock-out mice, behavioral, electrophysiological recording and other methods have proved that the promotion of myelin renewal alleviates the decreased memory ability and hippocampal electrophysiological abnormalities in AD mice
.
This paper provides new laboratory evidence for understanding the changes and function of myelin sheath in the pathogenesis of AD (Figure 1)
.
Figure 1: Summary of main results.
Both existing studies and this paper have found that AD human brain specimens and AD model mouse brains have a wide reduction in total myelin sheath, and AD model mouse myelin sheath reduction occurs similarly to the decline in learning and memory ability.
(7 months old)
.
It is generally believed that the OPC differentiation disorder and abnormal myelination of the AD brain are one of the main reasons for the decrease of the total amount of myelin
.
In this paper, the researchers constructed APP/PS1; NG2-CreERT; Tau-mGFP fluorescent reporter mice to mark and observe the newborn myelin sheath, which was induced at the initial stage of memory decline (7 months of age) in APP/PS1 mice
.
Three months later, compared with controls of the same age, it was unexpectedly found that more new myelin sheaths appeared in the hippocampus, cortex, and corpus callosum of the brains of AD mice
.
It indicates that the remyelination of the brain of AD mice may be compensated by extensive demyelination, which is similar to the myelin repair process of other demyelinating diseases (such as multiple sclerosis)
.
In order to clarify the degradation of the formed myelin sheath and whether the newly formed myelin sheath can accumulate, the researchers constructed APP/PS1; PLP-CreERT; mT/mG fluorescent reporter mice
.
Myelin sheath (GFP+) was formed by the induction marker at the age of 2-4 months, and the material was taken at 13 months old, combined with MBP staining, it was observed that the myelin sheath (GFP+/MBP+, marked in blue) in the brains of AD mice was greatly reduced compared with the control group , But at the same time there is more newly formed myelin (GFP-/MBP+, marked in red) (Figure 2), indicating that the new myelin in the brain of AD mice can accumulate and increase
.
The above results suggest that although the new myelin sheath can accumulate and increase in the brain of AD mice, the rapid degeneration of the myelin sheath has formed, resulting in a decrease in the total amount of myelin sheath
.
Figure 2.
The accumulation of new myelin in the brain of APP/PS1 mice.
Because there is no effective method to prevent myelin degeneration, the researchers imagine that by enhancing the formation of endogenous myelin, it is possible to better repair the myelin, and Improve AD-related learning and memory decline
.
The research team confirmed in previous studies that the muscarinic receptor 1 (M1R) negatively regulates OPC differentiation and myelination, and promotes myelination in both developing and aging brains [5, 6]
.
Therefore, the researchers constructed APP/PS1; NG2-CreERT; M1R fl/fl; Tau-mGFP mice to promote the myelination of AD mice by inducing the expression of M1R knocked out of OPC
.
The M1R in the OPC of APP/PS1 mice aged 7-8 months was induced to knock out, and the results showed that the new myelin sheath in the mouse brain increased significantly after 3 and 6 months compared with the control group, and the total amount of myelin was recovered significantly
.
It is worth noting that the new myelin sheath increased linearly and continuously in March, June and September after induction of APP/PS1;M1R cKO mice
.
The above research results show that promoting myelination can effectively improve AD-related myelin degeneration
.
The researchers used the Morris water maze and new object recognition methods to further prove that promoting myelin renewal can significantly improve the cognitive dysfunction of APP/PS1 mice
.
Using methods such as in vivo recording, it has also been found that after increased myelination in M1R knockout mice, it can enhance memory-related neuron activation and the hippocampal sharp wave ripple (SWR) activity during slow-wave sleep
.
The treatment of APP/PS1 mice with the pro-myelination drug-clemastine also has a similar protective effect
.
In summary, this paper reveals the dynamic changes of AD-related myelin sheath, and proposes a treatment strategy to promote myelination to alleviate AD-related cognitive dysfunction
.
The first author of this article is Chen Jingfei, a 2018 PhD student in Histology and Embryology at the Army Military Medical University, Liu Kun, a 2018 master student in Developmental Biology, and Professor Hu Bo from the Department of Physiology; Professor Jonah R.
Chan, University of California, San Francisco, Army Professor Lan Xiao and Professor Feng Mei (lead contact) of the Military Medical University are the corresponding authors of this article
.
Figure 6.
Creative diagram of AD and myelin sheath (by Luo Yan) Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
05.
012 Reprint instructions [Non-original article] The copyright of this article belongs to the author of the article, and individuals are welcome Reposting and sharing, reprinting without permission is prohibited, the author has all legal rights, offenders must be investigated
.
References [1]BRUN A, ENGLUND E.
A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study [J].
Ann Neurol, 1986, 19(3): 253-62.
doi:10.
1002/ana.
410190306 [2]MIGLIACCIO R, AGOSTA F, POSSIN KL, et al.
White matter atrophy in Alzheimer's disease variants [J].
Alzheimers Dement, 2012, 8(5 Suppl): S78-87.
e1-2.
doi:10.
1016/j .
jalz.
2012.
04.
010[3]STEADMAN PE, XIA F, AHMED M, et al.
Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice [J].
Neuron, 2020, 105(1): 150-64.
e6.
doi :10.
1016/j.
neuron.
2019.
10.
013[4]PAN S, MAYORAL SR, CHOI HS, et al.
Preservation of a remote fear memory requires new myelin formation [J].
Nat Neurosci, 2020, 23(4): 487 -99.
doi:10.
1038/s41593-019-0582-1[5]WANG F, REN SY, CHEN JF, et al.
Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory [J].
Nat Neurosci, 2020, 23(4): 481-6.
doi:10.
1038/s41593-020-0588-8[6]WANG F, YANG YJ, YANG N, et al.
Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia [J].
Neuron, 2018, 99(4): 689-701.
e5.
doi:10.
1016/j.
neuron.
2018.
07.
017
