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Brain cleaners reprogrammed to eradicate Alzheimer’s disease

To summarize: Using CRISPR gene editing, researchers were able to control microglia and reverse their Alzheimer’s-related toxic state and put them back on track.

resource: UCSF

The discovery of how damaged brain cells can be converted from a diseased state to a healthy state offers a potential new avenue for treating Alzheimer’s and other forms of dementia, according to a new study by UCSF researchers.

The study focused on microglia, cells that stabilize the brain by removing damaged neurons and plaques of proteins commonly associated with dementia and other brain disorders.

Although changes in these cells are known to play an important role in Alzheimer’s and other brain diseases, these cells are under-studied, said senior author Martin Kampmann, Ph.D., on the study, published Aug. 11 in . Nature Neuroscience.

“Now, using a new CRISPR method we’ve developed, we can reveal how to actually control these microglia so that they stop doing toxic things and start doing their vital cleaning job again,” he said. “This capability opens up the opportunity for an entirely new approach to treatment.”

Harnessing the brain’s immune system

Most of the genes known to increase Alzheimer’s risk work through microglia. Therefore, these cells have a major impact on how these neurodegenerative diseases work, Kampmann said.

Microglia act as the brain’s immune system. Ordinary immune cells cannot cross the blood-brain barrier, so the job of healthy microglia is to remove waste and toxins and keep neurons in top shape. When microglia begin to lose their way, the result can be brain inflammation and damage to neurons and the networks they form.

For example, in some cases, microglia begin to remove synapses between neurons. While this is a normal part of a person’s brain development during childhood and adolescence, it can have disastrous effects on the adult brain.

Over the past five years or so, many studies have observed and analyzed these different microglial states, but have not been able to characterize the genetics behind them.

Kampmann and his team wanted to determine exactly which genes are involved in specific states of microglial activity and how each of these states is regulated. Armed with this knowledge, they can turn genes on and off to put the wayward cells back on the right track.

From Advanced Genomics to the Holy Grail

Achieving this task requires overcoming fundamental barriers that prevent researchers from controlling gene expression in these cells. For example, microglia are highly resistant to the most common CRISPR technique, which involves delivering the required genetic material into cells by using a virus.

To overcome this, Kampmann’s team induced stem cells donated by human volunteers to become microglia and confirmed that these cells functioned just like their normal human counterparts. The team then developed a new platform that incorporates a form of CRISPR that allows researchers to turn individual genes on and off — Kampmann played a major role in development — and reads that indicate individual microglia function and state The data.

The study focused on microglia, cells that stabilize the brain by removing damaged neurons and plaques of proteins commonly associated with dementia and other brain disorders.Image is in the public domain

From this analysis, Kampmann and his team identified genes that affect the cells’ ability to survive and proliferate, how actively cells produce inflammatory substances, and how aggressively cells prune synapses.

And because scientists have identified which genes control these activities, they are able to reset the genes and restore diseased cells to a healthy state.

With this new technology, Kampmann plans to study how to control the relevant state of microglia by targeting the cells with existing drug molecules and testing them in preclinical models. He hopes to find specific molecules that act on the genes necessary to push diseased cells back to a healthy state.

Once the right genes are flipped, the “repaired” microglia are likely to resume their duties, removing plaques associated with neurodegenerative disease and protecting synapses, rather than tearing them apart, Kampmann said.

“Our research provides a blueprint for new treatments,” he said. “It’s kind of like the Holy Grail.”

funds: This work was funded in part from NIH grants DP2 GM119139, U01 MH115747, U54 NS100717, R01 AG051390, F30 AG066418, F30 AG062043, and ZO1 AG000534-02.For other funding see Research

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author: Additional authors include: UCSF’s Nina Dräger, Sydney Sattler, Olivia M. Teter, Kun Leng, Jason Hong, Giovanni Aviles, Claire D. Clelland, Lay Kodama, and Li Gan. For other authors, see this study.

About this Alzheimer’s disease and gene editing research news

author: Robin Max
resource: UCSF
touch: Robin Marks – UCSF
picture: Image is in the public domain

Original research: Open access.
“CRISPRi/a platform in human iPSC-derived microglia reveals regulators of disease states”, Martin Kampmann et al. Nature Neuroscience


Abstract

CRISPRi/a platform in human iPSC-derived microglia reveals regulators of disease states

Microglia are emerging as a key driver of neurological disease. However, we lack a systematic understanding of the underlying mechanisms.

Here, we present a screening platform to systematically elucidate the functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia.

We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and performed three screens against the ‘druggable genome’. These screens revealed genes that control microglial survival, activation, and phagocytosis, including those associated with neurodegeneration.

Screens using single-cell RNA sequencing as a readout showed that these microglia adopted a range of states similar to those observed in the human brain and identified regulators of these states. Disease-related states characterized by osteopontin (SPP1) expression are selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition.

Therefore, our platform can systematically uncover regulators of microglial state, enabling their functional characterization and therapeutic targeting.

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