New CRISPR application uncovers Alzheimer's disease mechanisms

A form of CRISPR which allows genes to be turned on and off has been used to investigate the role of genetic variants that affect the microglia cells, in the development of Alzheimer's disease.

Microglia cells are the 'clean-up crew' of the brain; they sweep up debris and unwanted proteins which build up in the brain during different neurodegenerative diseases. Microglia are responsible for preventing amyloid plaque formation for example, which can occur in the brains of Alzheimer's disease patients. Gene variants in microglia have been identified that are associated with an increased risk of Alzheimer's disease (see BioNews 1140). But how these specific variants might be affecting the various functions or states of microglia is unknown. In a new study, published in Nature Neuroscience, researchers investigated this connection.

'These cells are understudied, despite the fact that changes in them are known to play a significant role in Alzheimer's,' said Dr Martin Kampmann, co-senior author of the study and associate professor at the Weill Institute for Neurosciences from the University of California, San Francisco.

In the study, the researchers outlined a method they had developed for creating microglia in the laboratory using induced pluripotent human stem cells. They used a new CRISPR application to target specific genes known to be associated with Alzheimer's disease, essentially turning these genes on and off to see how that affected the function and state of the microglia.

This new CRISPR application has been named CRISPR interference/activation, or CRISPRi/a, and allows data to be collected on how cells behave when a specific gene is activated or silenced.

Using this approach in their induced human microglia cells, the researchers were able to identify which genes regulated which functional states of the microglia. For example, they identified which genes regulated microglial survival, inflammatory activation and the microglial consumption of synapses (the connections between brain cells), which is known to go awry during Alzheimer's disease. Furthermore, using their new knowledge of the genes linked with functional states, they were then able to genetically target microglia in an activated diseased state and revert the cells to a healthier state.

The data collected in the experiment could be used to help identify which existing drugs could be tested as preventative treatments for Alzheimer's disease in pre-clinical models, the authors suggest.

Dr Kampmann said: 'Now... we can uncover how to actually control these microglia, to get them to stop doing toxic things and go back to carrying out their vitally important cleaning jobs. This capability presents the opportunity for an entirely new type of therapeutic approach.'