Nat Neurosci︱ For the first time! Neuron ApoE affects the new mechanism of AD pathology by affecting immune response genes

Written by Wang Sizhen, edited by Wang Sizhen, Wang Sizhen Alzheimer's disease (AD), commonly known as Alzheimer's disease, is a common neurodegenerative disease that often occurs in the elderly.

There is currently no effective treatment.

Apolipoprotein E (ApoE) is a polymorphic protein that binds to lipid particles and participates in the transformation and metabolism of lipoproteins [1].

There are three subtypes of ApoE, namely ApoE2, ApoE3, and ApoE4.
Among them, ApoE4 is a major genetic risk factor for AD, which can increase the risk of AD and advance the age of onset of AD [2-3].

 In the central nervous system, ApoE protein is mainly produced from astrocytes, but under some stress, injury and aging conditions, neurons will also produce ApoE; neuron ApoE4 can induce tau protein pathology, leading to neuroinflammation and nerves Meta damage, and impairs learning and memory function [4-6].

 In AD, compared with neurons in other brain regions, neurons in the hippocampus and entorhinal cortex are more susceptible, that is, more susceptible to disease factors.
However, among these susceptible neurons, some neurons are very susceptible.
Fast death, while others show strong recovery capabilities, including the ability to restore their original mechanisms, that is, neurons undergo different neurodegeneration in AD [2, 7-8].

In addition to AD, there are similar phenomena in many other neurodegenerative diseases.

So, what is the driving mechanism behind this difference in susceptibility or this selective neurodegeneration? We are not very clear about the relevant knowledge.

 May 6, 2021, in the latest paper published in Nature Neuroscience entitled Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease, Gladstone Institute of Neurological Disease (Gladstone Institute of Neurological Disease) Yadong Huang's research team discovered for the first time the relationship between the expression of ApoE in neurons and the expression of immune response factor MHC-I, and subsequently with tau pathology and selective neurodegeneration.


First, the researchers performed mononuclear RNA sequencing analysis on the hippocampus of female mice with ApoE genes (ApoE3 and ApoE4) of different ages.
They identified 16 different neuronal groups, including dentate gyrus granule cells, CA1/ CA2/CA3 vertebral body cells, etc.
, in these neuronal types, the knock-in expression of ApoE has a strong correlation with different neuron types, and the expression level of ApoE in different neurons is different.
These hints ApoE may be the main cause of cell-to-cell variation.

In the enrichment analysis of ApoE4 expression signaling pathways in these different types of neurons, it was found that ApoE4 is mainly involved in four types of cell signaling pathways: cell metabolism, neurodegeneration, unfolded protein response, DNA damage and repair, and immune response .

However, in non-neuronal cells such as astrocytes and oligodendrocyte precursor cells, the enrichment of these signaling pathways is weak, indicating that the effect of ApoE expression on cell signaling pathways depends on the cell type.

  So, are these cell signals also enriched in the brains of AD patients? Therefore, the author also performed mononuclear RNA sequencing analysis on the cortex of patients with mild cognitive impairment (MCI) and people with AD, and found that nearly 30% of neurons highly express ApoE, and the expression level is in different disease states and different neurons.
There are also differences in ApoE; at the same time, the related signaling pathways of ApoE expression in patients are 43% similar to those in mice, including the above-mentioned four types of cell signaling pathways.

These results indicate the consistency of the data analysis results of AD patients and ApoE knock-in mice and the similarity of the mechanisms involved in ApoE, and also imply the potential for disease treatment conversion from mouse models to human patients.

  What is the level and distribution of ApoE mRNA in different cell types? The author noted that there are significant differences in the expression and distribution of ApoE in different types of hippocampal neuron cells, and this difference is related to the age of the mice.

Specifically, in mouse granulosa cells and CA1 vertebral cells, the expression level of the subtype ApoE4 gene rose rapidly at 5 months of age and reached the highest level at about 10 months of age.
Then the expression level began to decline rapidly with increasing age.
The expression level drops to the lowest at 20 months of age; another subtype of ApoE, namely ApoE3, has a slower trend of expression changes, reaching the highest level at about 15 months of age, and then rapidly declines; in the somatostatin/paralbumin intermediate nerve In Yuan Dynasty, the expression of ApoE4 and ApoE3 showed a trend of decreasing first and then increasing.
The expression of ApoE3 decreased to the lowest at the age of the month, while the decrease rate of ApoE4-KI was faster and larger.

These data collectively indicate that neuronal ApoE, especially the subtype ApoE4, may play a causal role in the selective neuronal degeneration and loss associated with AD.

 The expression of ApoE in astrocytes has no such changes related to age and genotype.

In addition, the authors found that the neuronal groups (excitatory neurons and inhibitory neurons) that express ApoE highly correlated well with the early stage of the disease (that is, the stage of mild cognitive impairment), and that in the later stage of the disease (that is, AD dementia) Stage) This correlation decreases, and as the disease progresses, the number of neurons with high ApoE expression decreases, and the number decreases as the disease progresses.

 So, can the deletion of the ApoE gene alleviate or prevent neural propulsion? The authors found that in the neurons of aged ApoE knock-in mice, specifically knocking out the ApoE gene can prevent the loss of neurons, synapses, and hippocampus, which highlights the role of ApoE in neurons in general neurodegeneration.
Key role.

 Immune signaling pathways play an important role in the pathogenesis of AD.

Here, the results also show that ApoE expression is also involved in related immune response pathways.
Among them, there is an immune signaling pathway gene MHC-I, which is abundantly expressed and has a strong correlation with ApoE expression.
The full name is major histocompatibility complex class I.
(The major histocompatibility complex class I) (Note: MHC is a collective name for a group of genes encoding animal major histocompatibility antigens.

Human MHC is called HLA (human leukocyte antigen), and mouse MHC is called H-2 [9]).

So, is there a causal relationship between ApoE expression and MHC expression in neurons? The results show that in mouse neurons, the expression of ApoE can induce the expression of MHC-I gene at the mRNA and protein levels; in the neurons of human patients, the phenomenon is similar, and the expression of ApoE can also cause MHC-I and MHC-I.
The expression of β2 microglobulin (B2M) gene is up-regulated, and B2M is a major regulator of MHC-I expression.

 At the end of the article, the author studied the relationship between neuronal ApoE expression and AD-related pathology.

First, experiments such as immunostaining have shown that the downstream of neuronal ApoE4 expression is related to AD-related tau protein pathology, and these tau protein pathologies are actually mediated by functional MHC-I expression in neurons.

Secondly, further verification found that in neurons, ApoE and MHC-I signal transduction play a role in the same or related pathways, and lead to AD-related tau pathology.

So, can reducing the expression level of MHC-I gene alleviate the pathology of tau? Researchers specifically knocked out B2M, the main regulator of MHC-I, in mouse hippocampal neurons to reduce the expression level of MHC-I.
They found that the pathology of tau protein was significantly improved, manifested as total tau and phosphorylated tau The expression level of Tau was reduced; moreover, in MCI and AD patients, it was also found that the MHC-I gene had a significant impact on the pathology of tau protein tangles, but not on the pathology of β-amyloid.

These results collectively indicate that reducing the functional expression of MHC-I can improve neuronal ApoE-induced tau pathology.

  Article model diagram: Neuron ApoE up-regulates MHC-I, which in turn drives tau pathology and neurodegeneration or loss of specific neurons and synapses (picture quoted from: Zalocusky, KA, Najm, R.
, Taubes, AL et al.
(2021) ) Nat Neurosci) Article conclusions and discussion In general, first, this study proposes a new model, that is, during the aging process, the increase of ApoE expression in neurons acts as a molecular switch that can trigger the immune response pathway in neurons The abnormal up-regulation of related gene MHC-I drives tau pathology and selective neurodegeneration in synapses and neurons.

This model is also in line with the hypothesis that during the process of aging-related neurodegeneration such as AD, the developmental role of microglia in the synapses is reactivated, leading to the loss of synapses and neurons.

 Second, this study also provides evidence that ApoE-induced overexpression of MHC-I in neurons may serve as a potential "eat me" signal, from stress neurons or damaged neurons to immune Potential signals from effector cells (such as microglia or T cells).

 Third, of course, this study raises many new questions about the role of ApoE in the pathogenesis of AD.

For example, under normal physiological and disease conditions, how is the expression of neuronal ApoE regulated? What are the molecular and cellular mechanisms that ApoE regulates the expression of MHC-I in neurons? Can the neuronal ApoE-MHC-I signal axis be able to Stressed or damaged neurons are transmitted to immune effector cells to perform the "eat me" process? How does the neuronal ApoE-MHC-I signal axis cause AD-related tau pathology? Regulation of the ApoE-MHC-I signal axis Are there patient gender differences and its role in the pathogenesis of AD? The answers to these questions will help clarify the pathogenesis of AD and better understand the selective neurodegeneration of neurons in neurodegenerative diseases.

  Fourth, this research also provides potential new targets for the development of drugs to prevent or treat AD selective neurodegeneration, for example, to reduce or block the expression of ApoE in neurons, and to disconnect ApoE-MHC- in neurons.
The I signal axis inhibits the mechanism by which MHC-I induces tau pathology, or blocks the presentation of MHC-I from neurons to immune effector cells.

In summary, this study revealed for the first time that ApoE in neurons can cause AD-related tau pathology through MHC-I.

Analyzing the internal neuron mechanism of AD's ApoE-MHC-I-tau pathological axis and exploring the potential role of microglia in this pathological process will be the key to future work.

  Original link: https://doi.
org/10.
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Neuron 98, 1141–1154 (2018).
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& Duff, KE Selective vulnerability in neurodegenerative diseases.
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21, 1350–1358 (2018).
[8] Andrews-Zwilling, Y.
et al.
Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice .
J.
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30, 13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews.
190: 95–122 (2002).
Plate making ︱ Wang Sizhen End of this articleAPOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types.
Neuron 98, 1141–1154 (2018).
[7] Fu, H.
, Hardy, J.
& Duff, KE Selective vulnerability in neurodegenerative diseases.
Nat.
Neurosci.
21, 1350–1358 (2018).
[8] Andrews-Zwilling, Y.
et al.
Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice .
J.
Neurosci.
30, 13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews.
190: 95–122 (2002).
Plate making ︱ Wang Sizhen End of this article& Duff, KE Selective vulnerability in neurodegenerative diseases.
Nat.
Neurosci.
21, 1350–1358 (2018).
[8] Andrews-Zwilling, Y.
et al.
Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice.
J.
Neurosci.
30, 13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews.
190: 95–122 (2002).
Plate making︱Wang Sizhen End of this article& Duff, KE Selective vulnerability in neurodegenerative diseases.
Nat.
Neurosci.
21, 1350–1358 (2018).
[8] Andrews-Zwilling, Y.
et al.
Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice.
J.
Neurosci.
30, 13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews.
190: 95–122 (2002).
Plate making︱Wang Sizhen End of this article13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews .
190: 95–122 (2002).
Plate Making︱Wang Sizhen End of this article13707–13717 (2010).
[9] Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H.
Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.
Immunological Reviews .
190: 95–122 (2002).
Plate Making︱Wang Sizhen End of this article