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Recently there is a highly rated movie, "Father Trapped in Time".
There are also many movies and television works describing cognitive impairment, but this film was shot from the perspective of the patient, which really makes Singularity a little scary.
In the blink of an eye, relatives become strangers and time is stolen.
Who can't be afraid of changing? Alzheimer's disease (AD) is such a terrible disease.
There are many risk factors for AD, and genetics, aging, and environment all play important roles.
In addition, many chronic diseases will also promote the progress of AD.
You may not think that these chronic diseases actually have a common underlying mechanism that affects AD, that is, "hypoxia"! Recently, a research team led by Javier Vitorica and Alberto Pascual of the Seville Institute of Biomedical Research published a paper in the journal Nature Aging[3], which revealed to a certain extent that non-genetic variables have an impact on Alzheimer’s The impact of disease progression.
Researchers have found that hypoxia stress, as a non-genetic cause of Alzheimer's disease, can affect the mitochondrial metabolism of microglia by regulating the activity of hypoxia-inducible factor 1 (HIF1).
Source | Screenshot of "Father Trapped in Time" Alzheimer's disease (Alzheimer's disease, AD) is a neurodegenerative disease that currently suffers more than 40 million patients worldwide [1].
The pathogenesis of AD is not clear, and it is mainly related to genetic and environmental factors.
In recent years, epidemiological surveys have shown that the proportion of AD patients with non-genetic variable factors, such as hypertension, obesity, diabetes and smoking, has reached 30-50% [2].
One of the main pathological manifestations of AD is β-amyloid deposition.
A large number of studies have found that when amyloid plaques appear, microglia will gather around them to build a protective barrier.
However, as the course of AD worsens, the defense effect of microglia will also be greatly reduced.
Why is the function of microglia weakened? Will environmental factors affect the protection of microglia on nerve cells? Microglia are responsible for the removal of amyloid plaques and will gather near the amyloid plaques.
During the removal process, they will consume oxygen and cause an oxygen-deficient environment.
Therefore, the researchers suspect that hypoxia is likely to be a cause of the weakened microglia.
The researchers first analyzed the brain slices of AD knockout mice through a combination of in situ hybridization and immunohistochemistry and found that in AD knockout mice, a transcription product, Hif1a mRNA, was found in Aβ plaques.
It is highly expressed in the surrounding microglia, and low in the microglia far away from the Aβ plaque.
Hif1a mRNA (brown) is highly expressed in AβAM (green), and blue is the nucleus.
It seems that it has a leg with microglia! So where is this HIF1 sacred? HIF1 is an oxygen-dependent transcriptional activator, which plays an important role in angiogenesis and mammalian development.
HIF1 is a multi-subunit complex, including HIF1α subunit and HIF1β subunit [4].
Among them, HIF1β subunit is stable and constitutively expressed, and HIF1α subunit will be degraded quickly after synthesis under normal conditions.
Under hypoxic conditions, the HIF1α subunit will become stable and interact with the co-activator P300/CBP to regulate downstream gene transcription activity.
The researchers systematically analyzed gene expression profiles containing hypoxia-induced response elements (HMM) and found that in other neurodegenerative diseases and aging gene knockout mice, the downstream target genes of HIF1 were not activated significantly, only in AD Transcription is active in knockout mice, further verifying that AβAM may be metabolically responding to the challenge of hypoxic environment through downstream signals mediated by HIF1.
In previous reports, HIF1 usually induces the conversion of aerobic mitochondrial respiration to glycolysis [5].
Interestingly, the researchers found that in AβAM, the abnormalities of HIF1-induced anaerobic glycolysis and aerobic respiration were accompanied by activation, and oxidative phosphorylation was up-regulated.
Compared with the control, the EM section of the hippocampus of AD knockout mice showed that the mitochondrial morphology was significantly prolonged, which all indicated the presence of local metabolic stress around the Aβ plaques.
The transcription of genes involved in aerobic respiration in AD microglia is up-regulated.
AD gene knockout mice have abnormal mitochondrial morphology and extension in the hippocampus.
By culturing microglia primary cells, the researchers found that continuous over-activation of HIF1 promotes microglia The cell cycle is blocked and the ability of AβAM to proliferate and accumulate around Aβ plaques in the body is reduced.
So how does this affect the actual disease manifestation? The researchers cultured 14-month-old AD knockout mice under normal oxygen (21% O2) and hypoxia (9% O2) conditions for 21 days for experiments.
The results found that under hypoxic conditions, mouse brain slices showed more Aβ plaque deposition, spreading and degeneration axons, further highlighting the correlation of variable AD risk factors related to HIF1 activation.
Continued hypoxia can cause a significant decrease in the number of microglia near the amyloid plaque.
Finally, the researchers performed RNA sequencing on different types of cells isolated from human brain samples from AD patients and found that, compared with other cells, HIF1α and its Downstream target genes are highly expressed in microglia, which is consistent with the results of mice and cultured cells.
It can be seen that in humans, the HIF1 signaling pathway is also closely related to the energy metabolism of microglia.
Previous studies on AD mainly started from the perspective of genetic screening, such as the susceptibility gene apoE4 (apolipoprotein E4).
The probability of individuals homozygous for apoE4 with a genotype of apoE4 is about 91% [6].
In recent years, people’s understanding of AD has been transformed into the overall investigation of the vascular neural network, because AD usually causes cardiovascular and cerebrovascular disorders and then causes hypoxia and nutrient uptake obstacles, angiogenesis and the stress regulation of the cellular microenvironment become A new direction for the treatment of AD.
In conclusion, this study reveals the important role of HIF1 signal transduction in mitochondrial metabolism in microglia adjacent to amyloid plaques.
At the same time, it also paves the way for finding pharmaceutical preparations that can improve the mitochondrial metabolic fitness of microglia to combat the stress exerted by Aβ plaques and block the further deterioration of AD.
Singularity is hiring everyone! Everybody Hi~! We need fresh blood to inject new energy into the singularity.
Come on, become the singularity cake and do a new job with us! These are the little friends we are currently looking for~ If you want to create and innovate with the singularity cakes, come join us.
Please send your resume and work (if any) to: hr@geekheal.
com or you can directly add to the WeChat (geekheal-xintan) of Geekheal-xintan for communication.
When adding friends, please note: recruitment + position + professional field.
We are waiting for you at Singularity.
References: 1.
Blennow K.
and Zetterberg H.
Biomarkers for Alzheimer's disease: current status and prospects for the future[J].
J Intern Med, 2018, 284(6): 643-6632.
Sala Frigerio C.
, Wolfs L .
, Fattorelli N.
, et al.
The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques[J].
Cell Rep, 2019, 27(4): 1293-1306.
e63.
March-Diaz Rosana, Lara-Ureña Nieves, Romero-Molina Carmen, et al.
Hypoxia compromises the mitochondrial metabolism of Alzheimer's disease microglia via HIF1[J].
Nature Aging, 2021, 1(4): 385-3994.
Wei J.
, Yang Y.
, Lu M.
, et al.
Recent Advances in the Discovery of HIF-1α-p300/CBP Inhibitors as Anti-Cancer Agents[J].
Mini Rev Med Chem, 2018, 18(4): 296-3095 .
Balamurugan K.
HIF-1 at the crossroads of hypoxia, inflammation, and cancer[J].
Int J Cancer, 2016, 138(5): 1058-666.
Nelson T.
J.
and Sen A.
Apolipoprotein E particle size is increased in Alzheimer's disease[J].
Alzheimers Dement (Amst), 2019, 11: 10-18
There are also many movies and television works describing cognitive impairment, but this film was shot from the perspective of the patient, which really makes Singularity a little scary.
In the blink of an eye, relatives become strangers and time is stolen.
Who can't be afraid of changing? Alzheimer's disease (AD) is such a terrible disease.
There are many risk factors for AD, and genetics, aging, and environment all play important roles.
In addition, many chronic diseases will also promote the progress of AD.
You may not think that these chronic diseases actually have a common underlying mechanism that affects AD, that is, "hypoxia"! Recently, a research team led by Javier Vitorica and Alberto Pascual of the Seville Institute of Biomedical Research published a paper in the journal Nature Aging[3], which revealed to a certain extent that non-genetic variables have an impact on Alzheimer’s The impact of disease progression.
Researchers have found that hypoxia stress, as a non-genetic cause of Alzheimer's disease, can affect the mitochondrial metabolism of microglia by regulating the activity of hypoxia-inducible factor 1 (HIF1).
Source | Screenshot of "Father Trapped in Time" Alzheimer's disease (Alzheimer's disease, AD) is a neurodegenerative disease that currently suffers more than 40 million patients worldwide [1].
The pathogenesis of AD is not clear, and it is mainly related to genetic and environmental factors.
In recent years, epidemiological surveys have shown that the proportion of AD patients with non-genetic variable factors, such as hypertension, obesity, diabetes and smoking, has reached 30-50% [2].
One of the main pathological manifestations of AD is β-amyloid deposition.
A large number of studies have found that when amyloid plaques appear, microglia will gather around them to build a protective barrier.
However, as the course of AD worsens, the defense effect of microglia will also be greatly reduced.
Why is the function of microglia weakened? Will environmental factors affect the protection of microglia on nerve cells? Microglia are responsible for the removal of amyloid plaques and will gather near the amyloid plaques.
During the removal process, they will consume oxygen and cause an oxygen-deficient environment.
Therefore, the researchers suspect that hypoxia is likely to be a cause of the weakened microglia.
The researchers first analyzed the brain slices of AD knockout mice through a combination of in situ hybridization and immunohistochemistry and found that in AD knockout mice, a transcription product, Hif1a mRNA, was found in Aβ plaques.
It is highly expressed in the surrounding microglia, and low in the microglia far away from the Aβ plaque.
Hif1a mRNA (brown) is highly expressed in AβAM (green), and blue is the nucleus.
It seems that it has a leg with microglia! So where is this HIF1 sacred? HIF1 is an oxygen-dependent transcriptional activator, which plays an important role in angiogenesis and mammalian development.
HIF1 is a multi-subunit complex, including HIF1α subunit and HIF1β subunit [4].
Among them, HIF1β subunit is stable and constitutively expressed, and HIF1α subunit will be degraded quickly after synthesis under normal conditions.
Under hypoxic conditions, the HIF1α subunit will become stable and interact with the co-activator P300/CBP to regulate downstream gene transcription activity.
The researchers systematically analyzed gene expression profiles containing hypoxia-induced response elements (HMM) and found that in other neurodegenerative diseases and aging gene knockout mice, the downstream target genes of HIF1 were not activated significantly, only in AD Transcription is active in knockout mice, further verifying that AβAM may be metabolically responding to the challenge of hypoxic environment through downstream signals mediated by HIF1.
In previous reports, HIF1 usually induces the conversion of aerobic mitochondrial respiration to glycolysis [5].
Interestingly, the researchers found that in AβAM, the abnormalities of HIF1-induced anaerobic glycolysis and aerobic respiration were accompanied by activation, and oxidative phosphorylation was up-regulated.
Compared with the control, the EM section of the hippocampus of AD knockout mice showed that the mitochondrial morphology was significantly prolonged, which all indicated the presence of local metabolic stress around the Aβ plaques.
The transcription of genes involved in aerobic respiration in AD microglia is up-regulated.
AD gene knockout mice have abnormal mitochondrial morphology and extension in the hippocampus.
By culturing microglia primary cells, the researchers found that continuous over-activation of HIF1 promotes microglia The cell cycle is blocked and the ability of AβAM to proliferate and accumulate around Aβ plaques in the body is reduced.
So how does this affect the actual disease manifestation? The researchers cultured 14-month-old AD knockout mice under normal oxygen (21% O2) and hypoxia (9% O2) conditions for 21 days for experiments.
The results found that under hypoxic conditions, mouse brain slices showed more Aβ plaque deposition, spreading and degeneration axons, further highlighting the correlation of variable AD risk factors related to HIF1 activation.
Continued hypoxia can cause a significant decrease in the number of microglia near the amyloid plaque.
Finally, the researchers performed RNA sequencing on different types of cells isolated from human brain samples from AD patients and found that, compared with other cells, HIF1α and its Downstream target genes are highly expressed in microglia, which is consistent with the results of mice and cultured cells.
It can be seen that in humans, the HIF1 signaling pathway is also closely related to the energy metabolism of microglia.
Previous studies on AD mainly started from the perspective of genetic screening, such as the susceptibility gene apoE4 (apolipoprotein E4).
The probability of individuals homozygous for apoE4 with a genotype of apoE4 is about 91% [6].
In recent years, people’s understanding of AD has been transformed into the overall investigation of the vascular neural network, because AD usually causes cardiovascular and cerebrovascular disorders and then causes hypoxia and nutrient uptake obstacles, angiogenesis and the stress regulation of the cellular microenvironment become A new direction for the treatment of AD.
In conclusion, this study reveals the important role of HIF1 signal transduction in mitochondrial metabolism in microglia adjacent to amyloid plaques.
At the same time, it also paves the way for finding pharmaceutical preparations that can improve the mitochondrial metabolic fitness of microglia to combat the stress exerted by Aβ plaques and block the further deterioration of AD.
Singularity is hiring everyone! Everybody Hi~! We need fresh blood to inject new energy into the singularity.
Come on, become the singularity cake and do a new job with us! These are the little friends we are currently looking for~ If you want to create and innovate with the singularity cakes, come join us.
Please send your resume and work (if any) to: hr@geekheal.
com or you can directly add to the WeChat (geekheal-xintan) of Geekheal-xintan for communication.
When adding friends, please note: recruitment + position + professional field.
We are waiting for you at Singularity.
References: 1.
Blennow K.
and Zetterberg H.
Biomarkers for Alzheimer's disease: current status and prospects for the future[J].
J Intern Med, 2018, 284(6): 643-6632.
Sala Frigerio C.
, Wolfs L .
, Fattorelli N.
, et al.
The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques[J].
Cell Rep, 2019, 27(4): 1293-1306.
e63.
March-Diaz Rosana, Lara-Ureña Nieves, Romero-Molina Carmen, et al.
Hypoxia compromises the mitochondrial metabolism of Alzheimer's disease microglia via HIF1[J].
Nature Aging, 2021, 1(4): 385-3994.
Wei J.
, Yang Y.
, Lu M.
, et al.
Recent Advances in the Discovery of HIF-1α-p300/CBP Inhibitors as Anti-Cancer Agents[J].
Mini Rev Med Chem, 2018, 18(4): 296-3095 .
Balamurugan K.
HIF-1 at the crossroads of hypoxia, inflammation, and cancer[J].
Int J Cancer, 2016, 138(5): 1058-666.
Nelson T.
J.
and Sen A.
Apolipoprotein E particle size is increased in Alzheimer's disease[J].
Alzheimers Dement (Amst), 2019, 11: 10-18
