Nature: Lu Bai's team at Tsinghua University has developed the world's first rat model that fully simulates human Alzheimer's disease

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 Alzheimer's drugs, but so far there is no cure (stop the disease progression) drug available

.

Few diseases can cause people's fear and helplessness more than Alzheimer's disease ( AD )

One of the reasons is that the AD animal model cannot simulate the real situation of human AD patients; therefore, many drug candidates are effective in animal models, but they are not effective in clinical trials of AD patients

 

 

Due to design or technical defects, it has not been possible to obtain an animal model that can truly fully reflect the pathological phenotype and disease mechanism of human AD , which has largely hindered AD research and clinical drug development

.

Due to design or technical defects, it has not been possible to obtain an animal model that can truly fully reflect the pathological phenotype and disease mechanism of human AD , which has largely hindered AD research and clinical drug development

Recently, the renowned neuroscientist, professor at Tsinghua University's School of Pharmacy, Lu white leadership team to achieve a major breakthrough in the field, to fully simulate the successful development of gene knock-rat model of Alzheimer's disease, related to the results of a few days ago to Article The format is published online in theCell Researchjournal

Long-term studies have shown that the precipitation of amyloid in the brain ( Aβ precipitation, commonly known as senile plaque) is the main pathological manifestation of AD patients and is also considered to be the main cause of AD .

Therefore, most of the AD models in the past used various transgenic technologies to express different mutant App genes in mice
.

In addition, transgenic technology has a series of inevitable defects: random insertion of human App mutant genes into the chromosomes of mice may disrupt the normal gene expression of the mouse at the insertion site; and the inserted mutant App genes may also be expressed in errors.

In this study, Professor Lu Bai’s team deliberately avoided the use of transgenic technology, and adopted CRISPR/Cas9 gene knock-in technology to realize the replacement of human App genes in rats , and carried Swedish , Beyreuther/Iberian and Arctic at the same time .
Three human family mutations, ( AppNL-GF ), do not change the temporal and spatial expression levels of App protein and its fragments in the brain
.

According to Dr.

The researchers conducted a detailed analysis of the App protein and multiple digested fragments in the AppNL-GF rat, and confirmed that the model avoids a variety of defects that are common in previous transgenic models .

In the brain of AD patients, in addition to the pathological deposition of Aβ , there are also abnormally high phosphorylated tau proteins in the form of oligomer fibers, forming the second pathological feature of AD : nerve fiber entanglement
.

The third significant change in the human AD brain is the progressive death of nerve cells and brain atrophy (shown as ventricular dilatation), which has also become the main indication for clinical diagnosis of AD with magnetic resonance(MRI).

Lu Bai’s team conducted a systematic study on the macroscopic and microscopic aspects of the brains of AppNL-GF rats and found that there are two main forms of cell death, both apoptosis and necroptosis , which occur in AD patients.
As the disease progresses, the weight of the brain tissue is reduced and the ventricles are expanded.
This is the first time that scientists have observed the expansion of the ventricles in animal models other than human AD .
Since AD was discovered for more than 100 years, scientists have not found the exact cause of neuronal death in AD patients.
The AppNL-GF rat provides a tool for studying this problem .

The method of gene knock-in to establish an AD animal model is not unattended
.
In 2014 , the Japanese scientist Saido's research group used almost the same strategy to create a knock-in AppNL-GF mouse model
.
Professor Lu's team made a head-to-head comparison study between the AppNL-GF rats developed by him and Saido 's AppNL-GF mice
.
A stunning result, although AppNL-GF mice demonstrated with AD comparison associated Aβ pathological phenotypes, and human AD pathology is similar, but AppNL-GF Rats different, which mouse model lacks The most critical pathological manifestation in the brain of AD patients is the continuous death of nerve cells and the resulting brain atrophy (shown as ventricular dilation)
.
In addition, tau protein pathology, another key feature of AD , was not shown in Saido mice .
This result suggests that AppNL-GF rats are closer to human AD
Animal model
.

The method of gene knock-in to establish an AD animal model is not unattended
.
In 2014 , the Japanese scientist Saido's research group used almost the same strategy to create a knock-in AppNL-GF mouse model
.
Professor Lu's team made a head-to-head comparison study between the AppNL-GF rats developed by him and Saido 's AppNL-GF mice
.
A stunning result, although AppNL-GF mice demonstrated with AD comparison associated Aβ pathological phenotypes, and human AD pathology is similar, but AppNL-GF Rats different, which mouse model lacks The most critical pathological manifestation in the brain of AD patients is the continuous death of nerve cells and the resulting brain atrophy (shown as ventricular dilation)
.
In addition, tau protein pathology, another key feature of AD , was not shown in Saido mice .
This result suggests that AppNL-GF rats are closer to human AD
Animal model
.

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 brains of AD patients, AppNL-GF rat brains also have significant neuroinflammation
.

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 brains of AD patients, AppNL-GF rat brains also have significant neuroinflammation
.

The deposition of toxins ( Aβ and tau )
in the AD brain and neuroinflammation can cause damage or loss of synapses .
Synaptic damage is also widely regarded as the key change point of AD 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 human AD .
With the current failures of most clinical treatments aimed at removing the toxic protein AD , repairing synaptic damage is a very promising treatment strategy .

The deposition of toxins ( Aβ and tau ) and neuroinflammation
in the AD brain can cause damage or loss of synapses .
Synaptic damage is also widely regarded as the key change point of AD 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 human immune AD .
With the current failures of most clinical treatments aimed at removing the toxic protein AD , repairing synaptic damage is a very promising treatment strategy .

As early as 2013 , Professor Lu Bai proposed a treatment method for synaptic repair and regeneration of neurodegenerative diseases in  Nature Reviews Neuroscience  .
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
.

As early as 2013 , Professor Lu Bai proposed a treatment method for synaptic repair and regeneration of neurodegenerative diseases in  Nature Reviews Neuroscience  .
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, through a variety of behavioral experimental paradigms, the researchers found that the model rats have all aspects of human AD 's spatial memory impairment, working memory impairment, and so on
.
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 AD model
.

Finally, through a variety of behavioral experimental paradigms, the researchers found that the model rats have all aspects of human AD 's spatial memory impairment, working memory impairment, and so on
.
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 AD 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 Wang Weiwen research group, the Jiang Tianzi research group of the Institute of Automation of the Chinese Academy of Sciences and the Hanwha research group worked together for several years to successfully establish the world's leading Alzheimer's disease 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 Wang Weiwen research group, the Jiang Tianzi research group of the Institute of Automation of the Chinese Academy of Sciences and the Hanwha research group worked together for several years to successfully establish the world's leading Alzheimer's disease model
.

Professor Lu Bai pointed out that 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.
It will be used to understand the pathogenesis of AD .
The discovery of sensitive biomarkers for early diagnosis of AD , especially the efficacy of innovative drugs, provides an indispensable tool
.

Professor Lu Bai pointed out that 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.
It will be used to understand the pathogenesis of AD .
The discovery of sensitive biomarkers for early diagnosis of AD , especially the efficacy of innovative drugs, provides an indispensable tool
.

Paper link:

Paper link:

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