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Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease.
With the degeneration and death of neurons, the memory and cognitive abilities of AD patients gradually decline [1].
However, not all neurons are affected equally, even in the same type of neurons, some cells are more likely to die, and some are safe.
The specific molecular mechanisms of selective degeneration and death within specific neuron types have also been plagued by scientists.
Recently, a new study published in the journal Nature Neuroscience showed that the selective degeneration of neurons is related to the regulation of intracellular immune response by apolipoprotein E (ApoE) [2].
Professor Huang Yadong, a senior researcher at the Gladstone Institute, and his research team used single-nuclear RNA sequencing (snRNA-seq) technology to study brain tissues in healthy and AD mouse models, and to analyze human brain tissues at different stages of neurodegenerative diseases.
Public data finally proves that neurons with high ApoE content are more likely to die, and this sensitivity is related to the regulation of ApoE's immune response in neurons, and affects the pathological characteristics of AD-related tau protein.
This is the first time to reveal that ApoE-induced MHC-I expression is causally related to AD-related tau protein pathology and tau protein-mediated neurodegeneration.
For a long time, ApoE gene has been the focus of AD research, and ApoE4 has the closest relationship with AD.
In the central nervous system, ApoE is mainly secreted by astrocytes, and expressed by pericytes, oligodendrocytes, choroid plexus and neurons under stress physiological conditions.
It is related to the metabolism of Aβ and the microtubule-associated protein tau.
The processes of AD mediated by neurodegeneration, neuroinflammatory response, synaptic integrity, lipid transport, glucose metabolism, etc.
are closely related [3].A study using a human ApoE gene knock-in or knock-out transgenic mouse model showed that compared with mice carrying ApoE2 and ApoE3 subtypes, mice carrying ApoE4 subtypes had significantly more brain atrophy, while ApoE lacked extremely It greatly reduced the loss of neurons and brain atrophy in mice.
At the same time, studies have shown that compared with the common ApoE3, carriers of single-copy ApoE4 have a three-fold increase in disease risk, while homozygous ApoE4 carriers have a direct increase of nearly ten times the risk of disease! In summary, ApoE4 subtypes increase the risk of AD in a dose-dependent manner [4].
However, there is no clear conclusion on how ApoE in neurons affects the risk of AD.
This study uses snRNA-seq technology to analyze the gene expression profiles of the same type of neurons and individual cells of different types of neurons in the brain tissues of mice and humans.
The results showed that even in the same type of neuron, there are significant differences in the ApoE expression level of different cells.
In addition, the patients develop from no cognitive impairment to mild cognitive impairment (MCI) and then to AD.
The proportion of neurons with high ApoE gene expression gradually increases and then decreases, that is, degeneration or death occurs.
This indicates that the expression level of neuron ApoE is related to the selective degeneration and death of specific types of neurons.
During the progression of AD, from no cognitive impairment (No CI) to dementia, the proportion of neurons with high ApoE gene expression in different types of neurons changes at the same time in healthy and sick patients or mouse brain tissues , The expression of neuronal ApoE is significantly related to cellular stress and immune response signaling pathways.
Based on the important role of immune response in the pathogenesis of AD, this study further studied the immune response signaling pathway related to ApoE expression and found that the major histocompatibility complex (MHC) gene was significantly enriched.
At the same time, the high expression level of ApoE can activate the expression of MHC-I gene.
In the signaling pathways related to neuronal ApoE expression, MHC genes are significantly enriched during brain development.
MHC-I participates in the signaling pathways that eliminate excessive synapses (connections between neurons), and can also trigger the immune system to eliminate receptors in the brain.
Damaged neurons and synapses.
Therefore, the expression of MHC-I indicates that neurons with high ApoE expression may be eliminated by the immune system.
The neurons with lower ApoE expression levels were intact.
Therefore, in the brain tissue of AD patients, the selective degeneration process in a specific neuron type is guided by the expression level of ApoE gene, that is, overexpression of ApoE leads to the up-regulation of the expression of MHC-I, causing an excessive immune response, and finally leading to the specific neuron type.
Selective degradation and death.
The above results indicate that by controlling the expression of MHC-I in neurons, ApoE may help determine which neuron should be recognized and eliminated by the immune system.
Picture from veer.
comtau protein is a good predictor of neurodegenerative diseases [5].
During AD, the phosphorylation of tau protein is unregulated, leading to mislocalization and abnormal aggregation, forming neurofibrillary tangles (NFTs), resulting in cell damage and death [6].
Studies have shown that ApoE plays an important role in the regulation of tau protein-mediated neurodegeneration, in which ApoE4 causes more serious damage, and the lack of ApoE has a protective effect [4].
The researchers further evaluated the effect of MHC-I on the pathological characteristics of AD-related tau protein and tau protein-mediated neurodegeneration.
The researchers knocked out the key component of MHC-I complex-2 microglobulin (B2M), inhibited the expression of MHC-I gene, and the expression level of ApoE did not change, the results showed that phosphorylated tau (p-tau) protein was mislocalized The phenomenon is significantly reduced, which indicates that the pathology of tau protein induced by MHC-I and ApoE has been significantly improved.
At the same time, the ApoE knockout experiment also showed similar results, indicating that neuronal ApoE and MHC-I affect AD-related tau pathology through the same or related pathways, further indicating that ApoE-induced MHC-I expression is associated with AD-related tau pathology There is a causal link between neurodegenerative disease.
This study proves that in the brains of AD patients, after stimulation by certain stress factors, the expression level of neuron ApoE increases abnormally, and causes the expression level of neuron MHC-I to be abnormally up-regulated, so that the cells produce "eat me" signals , Attacked by immune cells, and further drive AD-related tau pathology and selective degeneration or loss of neurons.
In summary, this research provides potential new targets for the development of drugs for the prevention or treatment of AD, such as reducing or blocking the expression of ApoE in neurons, blocking neurons from presenting MHC-I to immune effector cells, and inhibiting The mechanism by which MHC-I induces AD-related tau protein pathology has opened up a new way for the treatment of Alzheimer's disease.
Reference: [1] Huang Y, Mucke L.
Alzheimer mechanisms and therapeutic strategies.
Cell.
2012;148(6):1204-1222.
doi:10.
1016/j.
cell.
2012.
02.
040[2] Zalocusky KA, Najm R , Taubes AL, et al.
Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease [published online ahead of print, 2021 May 6].
Nat Neurosci.
2021;10.
1038/s41593-021-00851-3.
doi: 10.
1038/s41593-021-00851-3[3] Najm R, Jones EA, Huang Y.
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease.
Mol Neurodegener.
2019;14(1):24.
2019 Jun 11.
doi :10.
1186/s13024-019-0324-6[4] Shi Y, Yamada K, Liddelow SA, et al.
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.
Nature.
2017;549(7673):523- 527.
doi:10.
1038/nature24016[5] Pedersen JT, Sigurdsson EM.
Tau immunotherapy for Alzheimer's disease.
Trends Mol Med.
2015;21(6):394-402.
doi:10.
1016/j.
molmed.
2015.
03.
003[6] Ballatore C, Lee VM, Trojanowski JQ.
Tau-mediated neurodegeneration in Alzheimer's disease and related Disorders.
Nat Rev Neurosci.
2007;8(9):663-672.
doi:10.
1038/nrn2194 Author of this article | Liu Lingling, editor in charge | Ying Yuyan
With the degeneration and death of neurons, the memory and cognitive abilities of AD patients gradually decline [1].
However, not all neurons are affected equally, even in the same type of neurons, some cells are more likely to die, and some are safe.
The specific molecular mechanisms of selective degeneration and death within specific neuron types have also been plagued by scientists.
Recently, a new study published in the journal Nature Neuroscience showed that the selective degeneration of neurons is related to the regulation of intracellular immune response by apolipoprotein E (ApoE) [2].
Professor Huang Yadong, a senior researcher at the Gladstone Institute, and his research team used single-nuclear RNA sequencing (snRNA-seq) technology to study brain tissues in healthy and AD mouse models, and to analyze human brain tissues at different stages of neurodegenerative diseases.
Public data finally proves that neurons with high ApoE content are more likely to die, and this sensitivity is related to the regulation of ApoE's immune response in neurons, and affects the pathological characteristics of AD-related tau protein.
This is the first time to reveal that ApoE-induced MHC-I expression is causally related to AD-related tau protein pathology and tau protein-mediated neurodegeneration.
For a long time, ApoE gene has been the focus of AD research, and ApoE4 has the closest relationship with AD.
In the central nervous system, ApoE is mainly secreted by astrocytes, and expressed by pericytes, oligodendrocytes, choroid plexus and neurons under stress physiological conditions.
It is related to the metabolism of Aβ and the microtubule-associated protein tau.
The processes of AD mediated by neurodegeneration, neuroinflammatory response, synaptic integrity, lipid transport, glucose metabolism, etc.
are closely related [3].A study using a human ApoE gene knock-in or knock-out transgenic mouse model showed that compared with mice carrying ApoE2 and ApoE3 subtypes, mice carrying ApoE4 subtypes had significantly more brain atrophy, while ApoE lacked extremely It greatly reduced the loss of neurons and brain atrophy in mice.
At the same time, studies have shown that compared with the common ApoE3, carriers of single-copy ApoE4 have a three-fold increase in disease risk, while homozygous ApoE4 carriers have a direct increase of nearly ten times the risk of disease! In summary, ApoE4 subtypes increase the risk of AD in a dose-dependent manner [4].
However, there is no clear conclusion on how ApoE in neurons affects the risk of AD.
This study uses snRNA-seq technology to analyze the gene expression profiles of the same type of neurons and individual cells of different types of neurons in the brain tissues of mice and humans.
The results showed that even in the same type of neuron, there are significant differences in the ApoE expression level of different cells.
In addition, the patients develop from no cognitive impairment to mild cognitive impairment (MCI) and then to AD.
The proportion of neurons with high ApoE gene expression gradually increases and then decreases, that is, degeneration or death occurs.
This indicates that the expression level of neuron ApoE is related to the selective degeneration and death of specific types of neurons.
During the progression of AD, from no cognitive impairment (No CI) to dementia, the proportion of neurons with high ApoE gene expression in different types of neurons changes at the same time in healthy and sick patients or mouse brain tissues , The expression of neuronal ApoE is significantly related to cellular stress and immune response signaling pathways.
Based on the important role of immune response in the pathogenesis of AD, this study further studied the immune response signaling pathway related to ApoE expression and found that the major histocompatibility complex (MHC) gene was significantly enriched.
At the same time, the high expression level of ApoE can activate the expression of MHC-I gene.
In the signaling pathways related to neuronal ApoE expression, MHC genes are significantly enriched during brain development.
MHC-I participates in the signaling pathways that eliminate excessive synapses (connections between neurons), and can also trigger the immune system to eliminate receptors in the brain.
Damaged neurons and synapses.
Therefore, the expression of MHC-I indicates that neurons with high ApoE expression may be eliminated by the immune system.
The neurons with lower ApoE expression levels were intact.
Therefore, in the brain tissue of AD patients, the selective degeneration process in a specific neuron type is guided by the expression level of ApoE gene, that is, overexpression of ApoE leads to the up-regulation of the expression of MHC-I, causing an excessive immune response, and finally leading to the specific neuron type.
Selective degradation and death.
The above results indicate that by controlling the expression of MHC-I in neurons, ApoE may help determine which neuron should be recognized and eliminated by the immune system.
Picture from veer.
comtau protein is a good predictor of neurodegenerative diseases [5].
During AD, the phosphorylation of tau protein is unregulated, leading to mislocalization and abnormal aggregation, forming neurofibrillary tangles (NFTs), resulting in cell damage and death [6].
Studies have shown that ApoE plays an important role in the regulation of tau protein-mediated neurodegeneration, in which ApoE4 causes more serious damage, and the lack of ApoE has a protective effect [4].
The researchers further evaluated the effect of MHC-I on the pathological characteristics of AD-related tau protein and tau protein-mediated neurodegeneration.
The researchers knocked out the key component of MHC-I complex-2 microglobulin (B2M), inhibited the expression of MHC-I gene, and the expression level of ApoE did not change, the results showed that phosphorylated tau (p-tau) protein was mislocalized The phenomenon is significantly reduced, which indicates that the pathology of tau protein induced by MHC-I and ApoE has been significantly improved.
At the same time, the ApoE knockout experiment also showed similar results, indicating that neuronal ApoE and MHC-I affect AD-related tau pathology through the same or related pathways, further indicating that ApoE-induced MHC-I expression is associated with AD-related tau pathology There is a causal link between neurodegenerative disease.
This study proves that in the brains of AD patients, after stimulation by certain stress factors, the expression level of neuron ApoE increases abnormally, and causes the expression level of neuron MHC-I to be abnormally up-regulated, so that the cells produce "eat me" signals , Attacked by immune cells, and further drive AD-related tau pathology and selective degeneration or loss of neurons.
In summary, this research provides potential new targets for the development of drugs for the prevention or treatment of AD, such as reducing or blocking the expression of ApoE in neurons, blocking neurons from presenting MHC-I to immune effector cells, and inhibiting The mechanism by which MHC-I induces AD-related tau protein pathology has opened up a new way for the treatment of Alzheimer's disease.
Reference: [1] Huang Y, Mucke L.
Alzheimer mechanisms and therapeutic strategies.
Cell.
2012;148(6):1204-1222.
doi:10.
1016/j.
cell.
2012.
02.
040[2] Zalocusky KA, Najm R , Taubes AL, et al.
Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease [published online ahead of print, 2021 May 6].
Nat Neurosci.
2021;10.
1038/s41593-021-00851-3.
doi: 10.
1038/s41593-021-00851-3[3] Najm R, Jones EA, Huang Y.
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease.
Mol Neurodegener.
2019;14(1):24.
2019 Jun 11.
doi :10.
1186/s13024-019-0324-6[4] Shi Y, Yamada K, Liddelow SA, et al.
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.
Nature.
2017;549(7673):523- 527.
doi:10.
1038/nature24016[5] Pedersen JT, Sigurdsson EM.
Tau immunotherapy for Alzheimer's disease.
Trends Mol Med.
2015;21(6):394-402.
doi:10.
1016/j.
molmed.
2015.
03.
003[6] Ballatore C, Lee VM, Trojanowski JQ.
Tau-mediated neurodegeneration in Alzheimer's disease and related Disorders.
Nat Rev Neurosci.
2007;8(9):663-672.
doi:10.
1038/nrn2194 Author of this article | Liu Lingling, editor in charge | Ying Yuyan
