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▎Editor of WuXi AppTec's content team Few diseases can cause people's fear and helplessness more than Alzheimer's disease (AD)
.
In the past more than a century, researchers have carried out more than 400 clinical trials of AD drugs, but so far there is no drug that can cure the disease (stop the disease process)
.
The reason is that the existing animal models cannot fully simulate the real situation of human patients, resulting in many candidate drugs that are effective in animal models, but they have been used in clinical trials
.
Establishing an animal model that can fully reflect the pathological phenotype and disease mechanism of human Alzheimer's disease has always been a major problem that needs to be solved urgently in mechanism research and drug development in this field
.
Recently, a team led by a well-known neuroscientist and Professor Lu Bai from the School of Pharmacy of Tsinghua University has achieved a major breakthrough in this field and successfully developed a gene knock-in rat model that can fully simulate Alzheimer's disease
.
▲Relevant results were published online in Cell Research.
In this study, in order to avoid the inevitable defects of conventional transgenic technology, such as the wrong position of gene insertion, overexpression, and wrong gene expression distribution, Professor Lu Bai’s team adopted CRISPR/Cas9 genes Knock-in technology finally realized the replacement of human App genes in rats
.
As a precursor of amyloid (Aβ), some mutations in App will greatly accelerate the precipitation of Aβ and become the main pathological manifestation in the brain of Alzheimer's disease patients
.
In order to simulate human patients, the researchers realized the replacement of human App genes in rats and made them carry three human family mutations, namely AppNL-GF
.
According to Dr.
Pang Keliang, the first author of the paper, they screened more than 200 App mutation knock-in rat lines for this purpose, and finally screened an accurate AppNL-GF knock-in rat
.
▲Schematic diagram of constructing rat model: CRISPR/Cas9 gene knock-in technology was used to realize the replacement of human App genes in rats, and it also carried three human family mutations: Swedish, Beyreuther/Iberian and Arctic (picture source: reference) Data [1]) The researchers conducted a detailed analysis of the App protein and multiple digested fragments in the AppNL-GF rat, and confirmed that the model avoided a variety of defects that were common in the past transgenic models, and did not change the App protein and its The expression level of the fragment in time and space in the brain
.
Systematic pathology, cell biology and behavior studies have shown that compared with other existing animal models of Alzheimer's disease, this model shows more similar pathology and disease progression to human patients
.
The article shows that the rat model showed Aβ deposition at the age of two months, and showed a multi-brain area distribution with age, showing a progressive expansion very similar to the pathology of Aβ in the brain of human patients
.
In the brains of human patients, in addition to the pathological deposition of Aβ, there is also abnormally high phosphorylated tau protein in the form of oligomer fibers, forming the second pathological feature of AD: nerve fiber entanglement
.
The research team used four methods to prove that the rat model brain has hyperphosphorylated tau similar to humans, as well as pathological tau protein polymers
.
The researchers pointed out that it is generally difficult to observe both Aβ and tau pathologies in animal models.
The results of the new model reveal the potential relationship between Aβ pathology and tau pathology, providing strong evidence for the Aβ pathogenicity hypothesis.
It provides a direction for continuing to study the mechanism
.
The third significant change in the brain of human patients is the progressive death of nerve cells and brain atrophy (shown as ventricular dilatation), which has also become the main indication for clinical diagnosis with magnetic resonance (MRI)
.
The systematic study of AppNL-GF rats allowed scientists to observe the expansion of the brain ventricles in animal models other than humans for the first time
.
The researchers pointed out that this means that AppNL-GF rats can provide tools for studying the problem of neuronal death during Alzheimer's disease
.
▲The AD rat model showed ventricular expansion (picture source: reference [1]).
It is worth mentioning that in 2014, the research group of Japanese scientist Takaomi Saido (Dr.
Takaomi Saido) used almost the same strategy to produce genes.
Knock-in AppNL-GF mouse model
.
Through a head-to-head comparison study with AppNL-GF mice, Professor Lu Bai’s team pointed out that from the persistent death of nerve cells and the resulting brain atrophy, as well as another key feature of Alzheimer’s disease, tau protein pathology, etc.
Look, AppNL-GF rat is an animal model closer to human Alzheimer's disease
.
In addition, the researchers found a significant activation of glial cells in the AppNL-GF rat brain
.
In the hippocampus and cerebral cortex, microglia and astrocytes proliferate in large numbers with age
.
More importantly, microglia and astrocytes gather around Aβ plaques, which reflects that similar to the patient’s brain, AppNL-GF rat brain also has significant neuroinflammation
.
Image source: 123RF toxins (Aβ and tau) deposition and neuroinflammation can cause damage or loss of synapses
.
Synapse damage is also widely regarded as the key change point from pathophysiology to cognitive impairment, and it is the most predictive pathological feature related to cognitive status
.
Lu Bai's team used biochemical, immunohistochemical and three-dimensional electron microscopy techniques to prove that the rat model brain has synaptic damage and brain area characteristics similar to AD patients
.
Professor Lu Bai proposed a treatment method for synaptic repair and regeneration in neurodegenerative diseases as early as 2013.
With more and more research, it is recognized by the scientific, academic and industrial circles
.
The establishment of the AppNL-GF rat animal model will become an effective tool for validating new treatment strategies based on synapse repair
.
Finally, a variety of behavioral experimental paradigms show that this model rat has a full range of spatial memory impairment, working memory impairment and other common behavioral manifestations of human patients
.
More importantly, the researchers used an ingenious touch screen technology that is closer to human behavior to prove that AppNL-GF rats have obvious episodic memory impairment
.
The lack of episodic memory is the earliest and most common behavioral performance of AD patients, but it is difficult to apply touch screen technology in mouse models
.
Therefore, the results of this study also show another advantage of the rat model
.
This study was led by Pang Keliang, a graduate student/postdoctoral fellow of Professor Lu Bai of Tsinghua University, as the first author, and Dr.
Guo Wei, an associate researcher of Lu Bai’s team, as the co-corresponding author, in conjunction with the Per Nilsson research group of Karolinska Institutet in Sweden, and the Chinese Academy of Sciences Psychology Research The research group of Wang Weiwen, the research group of Jiang Tianzi of the Institute of Automation of the Chinese Academy of Sciences and the research group of Han Hua worked together for several years to successfully establish the world's leading AD model
.
"The AD rat model constructed this time fully exhibits the pathological characteristics of AD, and will play a certain role in promoting the successful clinical transformation of the currently stagnant AD global drug
.
" Professor Lu Bai pointed out
.
"It will provide an indispensable tool for understanding the pathogenesis of AD and discovering sensitive biomarkers for early diagnosis of AD, especially the efficacy of innovative drugs
.
Reference materials: [1] Keliang Pang et al.
, ( 2021) An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments.
Cell Reports.
Doi: https://doi.
org/10.
1038/s41422-021-00582-x[2] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC.
Single App knock-in mouse models of Alzheimer's disease.
Nat Neurosci.
Doi: 10.
1038/nn.
3697
.
In the past more than a century, researchers have carried out more than 400 clinical trials of AD drugs, but so far there is no drug that can cure the disease (stop the disease process)
.
The reason is that the existing animal models cannot fully simulate the real situation of human patients, resulting in many candidate drugs that are effective in animal models, but they have been used in clinical trials
.
Establishing an animal model that can fully reflect the pathological phenotype and disease mechanism of human Alzheimer's disease has always been a major problem that needs to be solved urgently in mechanism research and drug development in this field
.
Recently, a team led by a well-known neuroscientist and Professor Lu Bai from the School of Pharmacy of Tsinghua University has achieved a major breakthrough in this field and successfully developed a gene knock-in rat model that can fully simulate Alzheimer's disease
.
▲Relevant results were published online in Cell Research.
In this study, in order to avoid the inevitable defects of conventional transgenic technology, such as the wrong position of gene insertion, overexpression, and wrong gene expression distribution, Professor Lu Bai’s team adopted CRISPR/Cas9 genes Knock-in technology finally realized the replacement of human App genes in rats
.
As a precursor of amyloid (Aβ), some mutations in App will greatly accelerate the precipitation of Aβ and become the main pathological manifestation in the brain of Alzheimer's disease patients
.
In order to simulate human patients, the researchers realized the replacement of human App genes in rats and made them carry three human family mutations, namely AppNL-GF
.
According to Dr.
Pang Keliang, the first author of the paper, they screened more than 200 App mutation knock-in rat lines for this purpose, and finally screened an accurate AppNL-GF knock-in rat
.
▲Schematic diagram of constructing rat model: CRISPR/Cas9 gene knock-in technology was used to realize the replacement of human App genes in rats, and it also carried three human family mutations: Swedish, Beyreuther/Iberian and Arctic (picture source: reference) Data [1]) The researchers conducted a detailed analysis of the App protein and multiple digested fragments in the AppNL-GF rat, and confirmed that the model avoided a variety of defects that were common in the past transgenic models, and did not change the App protein and its The expression level of the fragment in time and space in the brain
.
Systematic pathology, cell biology and behavior studies have shown that compared with other existing animal models of Alzheimer's disease, this model shows more similar pathology and disease progression to human patients
.
The article shows that the rat model showed Aβ deposition at the age of two months, and showed a multi-brain area distribution with age, showing a progressive expansion very similar to the pathology of Aβ in the brain of human patients
.
In the brains of human patients, in addition to the pathological deposition of Aβ, there is also abnormally high phosphorylated tau protein in the form of oligomer fibers, forming the second pathological feature of AD: nerve fiber entanglement
.
The research team used four methods to prove that the rat model brain has hyperphosphorylated tau similar to humans, as well as pathological tau protein polymers
.
The researchers pointed out that it is generally difficult to observe both Aβ and tau pathologies in animal models.
The results of the new model reveal the potential relationship between Aβ pathology and tau pathology, providing strong evidence for the Aβ pathogenicity hypothesis.
It provides a direction for continuing to study the mechanism
.
The third significant change in the brain of human patients is the progressive death of nerve cells and brain atrophy (shown as ventricular dilatation), which has also become the main indication for clinical diagnosis with magnetic resonance (MRI)
.
The systematic study of AppNL-GF rats allowed scientists to observe the expansion of the brain ventricles in animal models other than humans for the first time
.
The researchers pointed out that this means that AppNL-GF rats can provide tools for studying the problem of neuronal death during Alzheimer's disease
.
▲The AD rat model showed ventricular expansion (picture source: reference [1]).
It is worth mentioning that in 2014, the research group of Japanese scientist Takaomi Saido (Dr.
Takaomi Saido) used almost the same strategy to produce genes.
Knock-in AppNL-GF mouse model
.
Through a head-to-head comparison study with AppNL-GF mice, Professor Lu Bai’s team pointed out that from the persistent death of nerve cells and the resulting brain atrophy, as well as another key feature of Alzheimer’s disease, tau protein pathology, etc.
Look, AppNL-GF rat is an animal model closer to human Alzheimer's disease
.
In addition, the researchers found a significant activation of glial cells in the AppNL-GF rat brain
.
In the hippocampus and cerebral cortex, microglia and astrocytes proliferate in large numbers with age
.
More importantly, microglia and astrocytes gather around Aβ plaques, which reflects that similar to the patient’s brain, AppNL-GF rat brain also has significant neuroinflammation
.
Image source: 123RF toxins (Aβ and tau) deposition and neuroinflammation can cause damage or loss of synapses
.
Synapse damage is also widely regarded as the key change point from pathophysiology to cognitive impairment, and it is the most predictive pathological feature related to cognitive status
.
Lu Bai's team used biochemical, immunohistochemical and three-dimensional electron microscopy techniques to prove that the rat model brain has synaptic damage and brain area characteristics similar to AD patients
.
Professor Lu Bai proposed a treatment method for synaptic repair and regeneration in neurodegenerative diseases as early as 2013.
With more and more research, it is recognized by the scientific, academic and industrial circles
.
The establishment of the AppNL-GF rat animal model will become an effective tool for validating new treatment strategies based on synapse repair
.
Finally, a variety of behavioral experimental paradigms show that this model rat has a full range of spatial memory impairment, working memory impairment and other common behavioral manifestations of human patients
.
More importantly, the researchers used an ingenious touch screen technology that is closer to human behavior to prove that AppNL-GF rats have obvious episodic memory impairment
.
The lack of episodic memory is the earliest and most common behavioral performance of AD patients, but it is difficult to apply touch screen technology in mouse models
.
Therefore, the results of this study also show another advantage of the rat model
.
This study was led by Pang Keliang, a graduate student/postdoctoral fellow of Professor Lu Bai of Tsinghua University, as the first author, and Dr.
Guo Wei, an associate researcher of Lu Bai’s team, as the co-corresponding author, in conjunction with the Per Nilsson research group of Karolinska Institutet in Sweden, and the Chinese Academy of Sciences Psychology Research The research group of Wang Weiwen, the research group of Jiang Tianzi of the Institute of Automation of the Chinese Academy of Sciences and the research group of Han Hua worked together for several years to successfully establish the world's leading AD model
.
"The AD rat model constructed this time fully exhibits the pathological characteristics of AD, and will play a certain role in promoting the successful clinical transformation of the currently stagnant AD global drug
.
" Professor Lu Bai pointed out
.
"It will provide an indispensable tool for understanding the pathogenesis of AD and discovering sensitive biomarkers for early diagnosis of AD, especially the efficacy of innovative drugs
.
Reference materials: [1] Keliang Pang et al.
, ( 2021) An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments.
Cell Reports.
Doi: https://doi.
org/10.
1038/s41422-021-00582-x[2] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC.
Single App knock-in mouse models of Alzheimer's disease.
Nat Neurosci.
Doi: 10.
1038/nn.
3697
