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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us.
iNatureNetrin-1 is a family member of laminin-related secretory proteins, which mediates axon guidance and cell migration during neural development.
The T835M mutation in the netrin receptor UNC5C is the cause of advanced Alzheimer's disease (AD) and increases neuronal cell death.
However, it is not clear how this receptor is molecularly regulated in AD.
On April 16, 2021, Keqiang Ye of Emory University and Zhaohui Zhang of Wuhan University jointly published a research paper entitled "Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies" in Science Advances.
Studies have shown that delta secretase selectively cleaves UNC5C and promotes its pro-apoptotic activity, thereby promoting neurodegeneration in AD.
Netrin deficiency activates delta-secretase, which specifically cleaves UNC5C at residues N467 and N547, and enhances subsequent caspase-3 activation, thereby increasing neuronal cell death.
Blocking the delta secretase cleavage of UNC5C reduces the pro-apoptotic activity of the T835M mutant.
The viral expression of the δ-secretase truncated UNC5C fragment in APP/PS1 mice strongly accelerated the AD pathology and impaired learning and memory.
In contrast, deleting UNC5C from netrin-1 depleted mice can alleviate AD pathology and rescue cognitive impairment.
Therefore, delta-secretase will shorten UNC5C and increase its neurotoxicity, leading to the onset of AD.
Alzheimer's disease (AD) is the most common dementia, an age-dependent neurodegenerative disease.
Characteristic pathological signs include extracellular senile plaques and intraneuronal fibrillary tangles (NFT) mainly composed of amyloid β (Aβ) peptide deposits, which are mainly composed of hyperphosphorylated and truncated microtubule-associated protein Tau, accompanied by A large number of neurons are lost.
Aβ is produced by the sequential proteolysis of transmembrane APP (amyloid precursor protein) by β-secretase (BACE1) and γ-secretase.
Netrin and its receptors Unc5 and DCC (absent in colorectal cancer) regulate axon guidance and cell migration.
Netrin-1 is a trophic factor of the laminin family, which has anti-inflammatory and anti-apoptotic effects, and plays a key role in neurogenesis and morphogenesis of neural structures.
More and more evidence supports the involvement of netrin-1 in AD pathology.
For example, netrin-1 improves Aβ-mediated memory suppression and synaptic plasticity.
Netrin-1 was reduced in AD model rats induced by Aβ42.
It is worth noting that netrin-1 binds to APP and regulates its signal transduction, thereby triggering amyloid precursor protein intracellular domain (AICD)-dependent gene transcription.
This interaction inhibits the Aβ peptide in the brain slices of AD model mice.
produce.
In addition, brain administration of netrin-1 can improve AD pathology.
APP directly interacts with DCC receptors in the presence of netrin-1 and enhances intracellular signal transduction mediated by netrin-1, such as MAPK activation.
The inactivation of APP in mice is related to the decrease of commissural axon growth.
Therefore, APP functions as a core receptor of DCC to mediate axon guidance.
Recently, several rare genetic variants have been discovered in APP, TREM2 and UNC5C, which affect the risk of AD.
Because UNC5C is enriched in the hippocampus of the adult nervous system, it has been proposed that T835M UNC5C increases the risk of AD by increasing the sensitivity to neuronal cell death, especially in the vulnerable areas of the AD brain.
Brain structure is related to the polymorphism of UNC5C in AD.
The genetic variation of UNC5C affects neuroimaging in AD and is related to cerebral amyloid angiopathy, indicating that this receptor is indeed related to the pathology of AD.
Delta-secretase is an Acidosis-activated asparagine endopeptidase (AEP).
It is located in the endolysosome and its activation is mediated by pH-dependent auto-cleavage.
AEP can cleave SET (a deoxyribonuclease inhibitor), improve DNA nicking, and promote neuronal cell death.
In addition, SET acts as a PP2B inhibitor, and AEP cleavage of SET can increase the hyperphosphorylation of Tau in AD.
It is worth noting that the concentration of Tau N368 in the cerebrospinal fluid (CSF) samples of AD patients is longitudinally correlated with the Tau PET (positron emission tomography) signal in the AD brain, which is consistent with cognitive deficits.
In this study, it is reported that the decrease of netrin-1 in AD brain triggers the activation of delta-secretase, which subsequently cleaves the UNC5C receptor, thereby enhancing caspase-3 activity and neuronal apoptosis.
The overexpression of the δ-secretase truncated UNC5C fragment in the hippocampus of APP/PS1 mice accelerates AD pathology and cognitive deficits, and δ-secretase knockout or weakening of UNC5C cleavage can alleviate the AD pathology caused by netrin deficiency and Learning and memory disorders.
Therefore, delta-secretase selectively cleaves the UNC5C receptor and mediates its pathological role in the pathogenesis of AD.
Reference message: https://advances.
sciencemag.
org/content/7/16/eabe4499
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us.
iNatureNetrin-1 is a family member of laminin-related secretory proteins, which mediates axon guidance and cell migration during neural development.
The T835M mutation in the netrin receptor UNC5C is the cause of advanced Alzheimer's disease (AD) and increases neuronal cell death.
However, it is not clear how this receptor is molecularly regulated in AD.
On April 16, 2021, Keqiang Ye of Emory University and Zhaohui Zhang of Wuhan University jointly published a research paper entitled "Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies" in Science Advances.
Studies have shown that delta secretase selectively cleaves UNC5C and promotes its pro-apoptotic activity, thereby promoting neurodegeneration in AD.
Netrin deficiency activates delta-secretase, which specifically cleaves UNC5C at residues N467 and N547, and enhances subsequent caspase-3 activation, thereby increasing neuronal cell death.
Blocking the delta secretase cleavage of UNC5C reduces the pro-apoptotic activity of the T835M mutant.
The viral expression of the δ-secretase truncated UNC5C fragment in APP/PS1 mice strongly accelerated the AD pathology and impaired learning and memory.
In contrast, deleting UNC5C from netrin-1 depleted mice can alleviate AD pathology and rescue cognitive impairment.
Therefore, delta-secretase will shorten UNC5C and increase its neurotoxicity, leading to the onset of AD.
Alzheimer's disease (AD) is the most common dementia, an age-dependent neurodegenerative disease.
Characteristic pathological signs include extracellular senile plaques and intraneuronal fibrillary tangles (NFT) mainly composed of amyloid β (Aβ) peptide deposits, which are mainly composed of hyperphosphorylated and truncated microtubule-associated protein Tau, accompanied by A large number of neurons are lost.
Aβ is produced by the sequential proteolysis of transmembrane APP (amyloid precursor protein) by β-secretase (BACE1) and γ-secretase.
Netrin and its receptors Unc5 and DCC (absent in colorectal cancer) regulate axon guidance and cell migration.
Netrin-1 is a trophic factor of the laminin family, which has anti-inflammatory and anti-apoptotic effects, and plays a key role in neurogenesis and morphogenesis of neural structures.
More and more evidence supports the involvement of netrin-1 in AD pathology.
For example, netrin-1 improves Aβ-mediated memory suppression and synaptic plasticity.
Netrin-1 was reduced in AD model rats induced by Aβ42.
It is worth noting that netrin-1 binds to APP and regulates its signal transduction, thereby triggering amyloid precursor protein intracellular domain (AICD)-dependent gene transcription.
This interaction inhibits the Aβ peptide in the brain slices of AD model mice.
produce.
In addition, brain administration of netrin-1 can improve AD pathology.
APP directly interacts with DCC receptors in the presence of netrin-1 and enhances intracellular signal transduction mediated by netrin-1, such as MAPK activation.
The inactivation of APP in mice is related to the decrease of commissural axon growth.
Therefore, APP functions as a core receptor of DCC to mediate axon guidance.
Recently, several rare genetic variants have been discovered in APP, TREM2 and UNC5C, which affect the risk of AD.
Because UNC5C is enriched in the hippocampus of the adult nervous system, it has been proposed that T835M UNC5C increases the risk of AD by increasing the sensitivity to neuronal cell death, especially in the vulnerable areas of the AD brain.
Brain structure is related to the polymorphism of UNC5C in AD.
The genetic variation of UNC5C affects neuroimaging in AD and is related to cerebral amyloid angiopathy, indicating that this receptor is indeed related to the pathology of AD.
Delta-secretase is an Acidosis-activated asparagine endopeptidase (AEP).
It is located in the endolysosome and its activation is mediated by pH-dependent auto-cleavage.
AEP can cleave SET (a deoxyribonuclease inhibitor), improve DNA nicking, and promote neuronal cell death.
In addition, SET acts as a PP2B inhibitor, and AEP cleavage of SET can increase the hyperphosphorylation of Tau in AD.
It is worth noting that the concentration of Tau N368 in the cerebrospinal fluid (CSF) samples of AD patients is longitudinally correlated with the Tau PET (positron emission tomography) signal in the AD brain, which is consistent with cognitive deficits.
In this study, it is reported that the decrease of netrin-1 in AD brain triggers the activation of delta-secretase, which subsequently cleaves the UNC5C receptor, thereby enhancing caspase-3 activity and neuronal apoptosis.
The overexpression of the δ-secretase truncated UNC5C fragment in the hippocampus of APP/PS1 mice accelerates AD pathology and cognitive deficits, and δ-secretase knockout or weakening of UNC5C cleavage can alleviate the AD pathology caused by netrin deficiency and Learning and memory disorders.
Therefore, delta-secretase selectively cleaves the UNC5C receptor and mediates its pathological role in the pathogenesis of AD.
Reference message: https://advances.
sciencemag.
org/content/7/16/eabe4499
