Currently, the lack of knowledge of the biomolecular mechanisms involved in neurodegenerative diseases is a major obstacle in the search for suitable treatments. And although the amyloid cascade theory As the main cause of Alzheimer’s disease is increasingly controversial, researchers have attempted to use the CRISPR tool to slow the progression of protein accumulation in neurons. The deletion of a specific fragment of a gene then reduced the formation of amyloid plaques by 44% in mice. However, this result remains relatively mixed as there is not yet strong evidence indicating a reduction in symptoms of dementia.
CRISPR technology has provided many clues on the biomolecular mechanisms inducing Alzheimer’s. In particular, it has made it possible to identify precursor genes for the formation of amyloid plaques, one of the characteristics of the disease. Researchers have therefore previously attempted to target these genes in order to treat the disease. Despite these discoveries, no treatment has yet succeeded in effectively slowing down the progression of the symptoms of the pathology.
This is said to be a common obstacle to most neurodegenerative diseases. Surprisingly, specific groups of neurons are indeed more susceptible to neurodegeneration than other more resilient ones. Research efforts therefore focus on how these neurons are selectively involved in the progression of diseases such as Alzheimer’s. Potential gene therapies may be able to confer the same resilience capacity to all neurons.
However, it should be kept in mind that most previous gene-editing research (for the search for Alzheimer’s treatments) focused on removing DNA sequences implicated in the formation of amyloid plaques. However, this drastic “amputation” might have unpredictable negative consequences, given the usefulness of the genes in question.
The new study from the University of California, San Diego (USA) specifically targets the APP gene, a precursor of amyloid protein synthesis at synapses. By knocking out the gene in mice, neuroinflammation, cognitive impairment and a decrease in the number of neurons were observed. To mitigate these risks and preserve the “useful” functions of the APP gene, the researchers then opted for its partial modification by eliminating only a tiny fragment at the cellular level.
A reduction of amyloid plaques by 44%
Using the CRISPR technique, researchers in the new study eliminated a fragment located at the end of the APP gene in four one-and-a-half-month-old mice. Four other mice received scrambled sequences of CRISPR, that is to say that no particular gene was modified or deleted at the level of their brain cells. For the tests, all the mice were genetically modified to develop symptoms and characteristics of Alzheimer’s disease at around two months of age.
Once they reached two and a half years of age, the mice were euthanized in order to examine their brains as part of a necropsy. The researchers then discovered that those treated with the modified APP gene had on average 44% fewer amyloid plaques than those who were not treated. Additionally, levels of neuroinflammation-inducing proteins were regarding 40% lower. And since the disease-specific features would be more exacerbated in mice, the researchers believe that the results of their treatment would be potentially greater in humans.
Moreover, the results would be the same in mice modified to develop the disease even one year following the administration of the treatment. No side effects were observed, even in mice genetically modified before birth to lack the segment of the APP gene, implicated in the disease. On the contrary, the latter showed improved cognitive functions.
In order to be able to cross the blood-brain barrier to administer the gene treatment, the researchers used a harmless virus called adeno-associated virus (AVV). However, the ability of the virus to cross the protective barrier of the brain is not yet fully efficient, and researchers will still try to determine the exact number to introduce into the body in order to be able to deliver the treatment effectively. The next stage of research will also be to determine whether the treatment can lead to a reduction in symptoms of dementia. This step will be critical, as treatments aimed at reducing the formation of amyloid plaques generally fail to improve cognition in people with Alzheimer’s.