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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
.
A major obstacle to iNature Alzheimer's disease (AD) research is the lack of predictable and transformable animal models that reflect disease progression and drug efficacy
.
Transgenic mice overexpressing the amyloid precursor protein (App) gene showed non-physiological and ectopic expression of APP and its fragments in the brain, which was not observed in AD patients
.
App knock-in mice avoided some of these problems, but they did not show tau pathology and neuronal death
.
On November 17, 2021, Tsinghua University Lu Bai and Guo Wei jointly published a research paper entitled "An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments" in Cell Research.
The graduate student became a rat model containing three familiar App mutations and a humanized Aβ sequence knocked into the rat App gene
.
Without changing the levels of full-length APP and other APP fragments, the model exhibits pathology and disease progression similar to human patients: Aβ plaque deposition in related brain regions, microglia activation, and gliosis , Progressive synaptic degeneration, and AD-related cognitive deficits
.
Interestingly, the study observed tau pathology, neuronal apoptosis and necroptosis, and brain atrophy, which are rare in other APP models
.
The App knock-in rat model can be used as a useful tool for AD research, identifying new drug targets and biomarkers, and testing treatments
.
Alzheimer's disease (AD) is one of the most prominent age-related diseases and the main cause of disability in the elderly, whose memory, personality and other cognitive functions will gradually be impaired
.
AD has brought the heaviest social burden to the modern aging society
.
The pathological features of AD include senile plaques containing amyloid β peptide (Aβ), neurofibrillary tangles containing tau, progressive neuronal death, and neuroinflammation
.
Therefore, a cascade hypothesis of amyloid and tau has been proposed to explain the pathogenesis of AD
.
Although progress has been made in understanding certain pathogenic mechanisms, to date, efforts to develop disease-modifying therapies for AD have not been successful
.
Many factors may contribute to this, but one of the main obstacles seems to be the lack of animal models that can fully summarize the pathogenesis of the disease
.
Over the decades, hundreds of models have been developed, but few can truly reproduce the main neuropathological phenotypes seen in AD patients
.
This may be because a considerable number of candidate AD drugs that have been shown to be effective in AD animal models have failed in clinical trials
.
Most AD models are transgenic mice that overexpress human App genes
.
The most widely used are PDAPP and Tg2576 mice
.
However, these animal models is almost no neuronal death, no tau pathology
.
It is unclear whether the synaptic and behavioral defects seen in these animals are due to Aβ or other peptide energy products, which are derived from non-physiological expression and processing of APP
.
In addition, nearly 99% of the transgenic animal models have not mapped the insertion site of the transgene, so the observed phenotype cannot be entirely attributed to the biology of the transgene
.
Knock-in technology may circumvent some of these problems
.
Mice targeting a single mutation in the App gene showed only mild cognitive impairment without obvious AD pathology
.
When two or three familial AD mutations are introduced into mice, typical AD phenotypes include Aβ plaques, neuroinflammation (glial hyperplasia), and cognitive impairment
.
However, this model lacks two key features: tau pathology and neuronal death/brain atrophy
.
These shortcomings may hinder its application in basic research and drug development
.
Given the difference in brain size, cerebrospinal fluid (CSF) volume, and the most important genome structure and sequence differences between mice and humans, modeling AD in mice is not ideal
.
For decades, people have been trying to develop other animal models that are closer to humans in physiology, genetics, and morphology
.
Compared with mice, the genetic manipulation of rats lacks progress due to lack of tools
.
However, compared to mice, rats are more similar to humans in physiology and behavior
.
Their larger body size makes it easier to perform surgery and collect blood/cerebrospinal fluid samples
.
More importantly, the genomic similarity between rats and humans, such as alternative splicing of the tau gene, suggests that it may be more suitable for simulating AD
.
Several transgenic rat models have been generated, such as McGill-R-Thy1-APP, TgF344-AD, and APP + PS1, some of which show various aspects of AD pathology, including neuroinflammation, synaptic loss, and cognitive impairment
.
However, these models also have the same shortcomings of transgenic technology: non-physiological phenotypes due to overexpression of transgenes
.
Recently, knock-in technology has been applied to model AD in rats
.
Unfortunately, these rat models with a single App mutation leading to little Aβ deposition did not show obvious AD pathology
.
Therefore, there is a great need to develop alternative models that can faithfully summarize most of the pathogenic mechanisms in AD using knock-in technology
.
In this study, an App knock-in rat strain containing Swedish-Beyreuther/Iberian-Arctic mutations was generated using CRISPR/Cas9 technology
.
This rat model exhibits a comprehensive set of AD-related pathological, cellular, and behavioral phenotypes, which are rare in other APP models
.
It can be used as a useful tool to assist AD research and drug discovery
.
Reference message: https://
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
.
A major obstacle to iNature Alzheimer's disease (AD) research is the lack of predictable and transformable animal models that reflect disease progression and drug efficacy
.
Transgenic mice overexpressing the amyloid precursor protein (App) gene showed non-physiological and ectopic expression of APP and its fragments in the brain, which was not observed in AD patients
.
App knock-in mice avoided some of these problems, but they did not show tau pathology and neuronal death
.
On November 17, 2021, Tsinghua University Lu Bai and Guo Wei jointly published a research paper entitled "An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments" in Cell Research.
The graduate student became a rat model containing three familiar App mutations and a humanized Aβ sequence knocked into the rat App gene
.
Without changing the levels of full-length APP and other APP fragments, the model exhibits pathology and disease progression similar to human patients: Aβ plaque deposition in related brain regions, microglia activation, and gliosis , Progressive synaptic degeneration, and AD-related cognitive deficits
.
Interestingly, the study observed tau pathology, neuronal apoptosis and necroptosis, and brain atrophy, which are rare in other APP models
.
The App knock-in rat model can be used as a useful tool for AD research, identifying new drug targets and biomarkers, and testing treatments
.
Alzheimer's disease (AD) is one of the most prominent age-related diseases and the main cause of disability in the elderly, whose memory, personality and other cognitive functions will gradually be impaired
.
AD has brought the heaviest social burden to the modern aging society
.
The pathological features of AD include senile plaques containing amyloid β peptide (Aβ), neurofibrillary tangles containing tau, progressive neuronal death, and neuroinflammation
.
Therefore, a cascade hypothesis of amyloid and tau has been proposed to explain the pathogenesis of AD
.
Although progress has been made in understanding certain pathogenic mechanisms, to date, efforts to develop disease-modifying therapies for AD have not been successful
.
Many factors may contribute to this, but one of the main obstacles seems to be the lack of animal models that can fully summarize the pathogenesis of the disease
.
Over the decades, hundreds of models have been developed, but few can truly reproduce the main neuropathological phenotypes seen in AD patients
.
This may be because a considerable number of candidate AD drugs that have been shown to be effective in AD animal models have failed in clinical trials
.
Most AD models are transgenic mice that overexpress human App genes
.
The most widely used are PDAPP and Tg2576 mice
.
However, these animal models is almost no neuronal death, no tau pathology
.
It is unclear whether the synaptic and behavioral defects seen in these animals are due to Aβ or other peptide energy products, which are derived from non-physiological expression and processing of APP
.
In addition, nearly 99% of the transgenic animal models have not mapped the insertion site of the transgene, so the observed phenotype cannot be entirely attributed to the biology of the transgene
.
Knock-in technology may circumvent some of these problems
.
Mice targeting a single mutation in the App gene showed only mild cognitive impairment without obvious AD pathology
.
When two or three familial AD mutations are introduced into mice, typical AD phenotypes include Aβ plaques, neuroinflammation (glial hyperplasia), and cognitive impairment
.
However, this model lacks two key features: tau pathology and neuronal death/brain atrophy
.
These shortcomings may hinder its application in basic research and drug development
.
Given the difference in brain size, cerebrospinal fluid (CSF) volume, and the most important genome structure and sequence differences between mice and humans, modeling AD in mice is not ideal
.
For decades, people have been trying to develop other animal models that are closer to humans in physiology, genetics, and morphology
.
Compared with mice, the genetic manipulation of rats lacks progress due to lack of tools
.
However, compared to mice, rats are more similar to humans in physiology and behavior
.
Their larger body size makes it easier to perform surgery and collect blood/cerebrospinal fluid samples
.
More importantly, the genomic similarity between rats and humans, such as alternative splicing of the tau gene, suggests that it may be more suitable for simulating AD
.
Several transgenic rat models have been generated, such as McGill-R-Thy1-APP, TgF344-AD, and APP + PS1, some of which show various aspects of AD pathology, including neuroinflammation, synaptic loss, and cognitive impairment
.
However, these models also have the same shortcomings of transgenic technology: non-physiological phenotypes due to overexpression of transgenes
.
Recently, knock-in technology has been applied to model AD in rats
.
Unfortunately, these rat models with a single App mutation leading to little Aβ deposition did not show obvious AD pathology
.
Therefore, there is a great need to develop alternative models that can faithfully summarize most of the pathogenic mechanisms in AD using knock-in technology
.
In this study, an App knock-in rat strain containing Swedish-Beyreuther/Iberian-Arctic mutations was generated using CRISPR/Cas9 technology
.
This rat model exhibits a comprehensive set of AD-related pathological, cellular, and behavioral phenotypes, which are rare in other APP models
.
It can be used as a useful tool to assist AD research and drug discovery
.
Reference message: https://
