Empowering new drug discovery researchers to develop the first rat model that fully mimics human AD

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

Recently, a team led by a famous 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

In this study, in order to avoid the unavoidable defects of conventional transgenic technology, such as wrong gene insertion position, overexpression, and wrong distribution of gene expression, Professor Lu Bai's team adopted the CRISPR/Cas9 gene knock-in technology, and finally achieved the results in rats.

As a precursor of amyloid (Aβ), some mutations in App can greatly accelerate Aβ deposition, which becomes the main pathological manifestation in the brain of Alzheimer's disease patients

▲Schematic diagram of the construction of the rat model: CRISPR/Cas9 gene knock-in technology was used to replace the human App gene in the rat, and it also carried three human family mutations of Swedish, Beyreuther/Iberian and Arctic (Image source: Reference: data[1])

The researchers conducted a detailed analysis of the App protein and multiple restriction fragments in the AppNL-GF rat, confirming that the model avoids various defects commonly found in previous transgenic models, and does not change the expression of App protein and its fragments in the brain.

The article shows that the rat model showed Aβ deposition at the age of two months, and showed a multi-brain distribution with age, showing a progressive expansion of Aβ pathology very similar to the human patient brain

In human patient brains, in addition to the pathological deposition of Aβ, abnormally high phosphorylated tau protein exists in the form of oligomeric fibers, forming the second pathological feature of AD: nerve fiber entanglement

The third notable change in the human brain is the progressive death of nerve cells and brain atrophy (manifested as ventriculomegaly), which has become the main clinical indication for diagnosis with magnetic resonance imaging (MRI)

▲The AD rat model showed ventricle dilatation (Image source: Reference [1])

It is worth mentioning that in 2014, the research group of Japanese scientist Dr.

In addition, the researchers found significant activation of glial cells in the AppNL-GF rat brain

Toxins (Aβ and tau) deposition and neuroinflammation can lead to synaptic damage and even loss

Finally, a variety of behavioral experimental paradigms show that the model rats have a full range of behavioral manifestations common to human patients, such as spatial memory impairment and working memory impairment

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References:

[1] Keliang Pang et al.

[2] Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC.