CRISPR vs. Alzheimer's
Nanocomplexes with CRISPR relieved the symptoms of Alzheimer's disease in mice
Daria Spasskaya, N+1
Korean scientists were able to introduce mutations in the DNA of mature neurons in the brains of mice with a model of Alzheimer's disease and thereby mitigate the symptoms of the disease in adult animals. This was done with the help of nanocomplexes with the Cas9 protein, "charged" against the gene involved in the development of the disease, which were injected into the brain of mice. Article by Park et al. In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficiencies in mouse models of Alzheimer's disease is published in the journal Nature Neuroscience.
Despite the fact that mutations in DNA are not always the cause of the development of neurodegenerative diseases, scientists consider directed control of gene expression in neurons as a promising means of alleviating the symptoms of these diseases. For example, suppression of the expression of huntingtin genes (in another transcription – huntingtin) and ataxin-2 using antisense oligonucleotides stopped neurodegeneration in animals with ataxia and Huntington's disease. And turning off the gene in the brain using the CRISPR-Cas9 genome editing system relieved the animals of some of the symptoms of autism.
In a new paper, scientists from Dongguk University of South Korea chose Alzheimer's disease as a model of neurodegenerative disease and demonstrated that introducing a mutation into the DNA of mature neurons using the CRISPR-Cas9 system can stop the development of the disease.
The pathogenesis of Alzheimer's disease is based on the formation of amyloid plaques from a small protein called beta-amyloid. It is formed from a precursor protein with the participation of the beta-secretase enzyme. The researchers suggested that reducing the expression of the beta-secretase-encoding gene Bace1 in the brain would help prevent the accumulation of beta-amyloid.
To do this, the authors of the work tried to turn off Bace1 using CRISPR-Cas9 in the hippocampus of model animals – 5XFAD transgenic mice carrying several "family" mutations in the genome that lead to Alzheimer's disease. The finished genome editing system was delivered directly to the brain by injection. In order for the Cas9 protein charged with a guide RNA against the Bace1 gene to penetrate into neurons, it was mixed with the amphiphilic peptide R7L10. The resulting nanocomplexes were injected into the brains of mice. Previously, scientists tested on cell lines and a reporter gene that the system works as intended.
Four weeks after the injection, the expression of the Bace1 gene in the hippocampus decreased by 70 percent in the model mice compared to the control mice who were not treated with anything (there were 9 to 12 mice in the groups). The effect was accompanied by a significant decrease in the amount of beta-amyloid. In addition to the fact that the formation of plaques in neurons slowed down in mice, they coped with tasks in the maze much better than control animals and had better memory, that is, therapy helped them preserve cognitive abilities.
Reduction of beta-secretase expression (in red) after editing (bottom panel).
Reduction of the number of amyloid plaques (green) in edited mice (left panel).
The authors tested the system on another mouse model of Alzheimer's disease and confirmed that the approach works regardless of the model. However, scientists also state that the formation of plaques in Alzheimer's disease in humans is not limited to one part of the brain, so such therapy would be more useful for "localized" diseases, such as Parkinson's disease.
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