Reprogramming the Brain’s Cleaning Crew to Mop Up Alzheimer’s Disease

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Overview: Using CRISPR gene editing, researchers were able to control microglia and reverse their toxic state associated with Alzheimer’s disease and put them back on track.

Source: UCSF

The discovery of how to move damaged brain cells from a diseased state to a healthy one offers a potential new path to treating Alzheimer’s disease and other forms of dementia, according to a new study from researchers at UC San Francisco.

The research focuses on microglia, cells that stabilize the brain by clearing damaged neurons and the protein plaques often associated with dementia and other brain diseases.

These cells have not been studied enough, despite the fact that changes in them play an important role in Alzheimer’s disease and other brain diseases, said Martin Kampmann, PhD, senior author of the study, which appears Aug. Nature Neuroscience.

“Now, using a new CRISPR method we’ve developed, we can discover how to actually control these microglia so that they stop doing toxic things and go back to doing their essential cleaning tasks,” he said. “This opportunity opens up the possibility for an entirely new type of therapeutic approach.”

Making use of the brain’s immune system

Most of the genes known to increase the risk of Alzheimer’s disease work through microglial cells. So these cells have a significant impact on how such neurodegenerative diseases progress, 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 clear out waste and toxins so that neurons continue to function at their best. When microglia get lost, it can lead to brain inflammation and damage to neurons and the networks they form.

For example, under certain conditions, microglia will begin to remove synapses between neurons. While this is a normal part of brain development in a person’s childhood and adolescence, it can have disastrous consequences for the adult brain.

Over the past five years, many studies have observed and profiled these different microglial states, but have been unable to characterize the genetics behind them.

Kampmann and his team wanted to identify exactly which genes are involved in specific states of microglial activity and how each of those states is regulated. With that knowledge, they could switch genes on and off and put wayward cells back on track.

From Advanced Genomics to a Holy Grail

To accomplish that task, fundamental obstacles had to be overcome that prevented researchers from controlling gene expression in these cells. For example, microglia are highly resistant to the most common CRISPR technique, in which the desired genetic material is introduced into the cell by using a virus to deliver it.

To remedy this, Kampmann’s team coaxed stem cells donated by human volunteers to become microglia and confirmed that these cells function like their regular human counterparts. The team then developed a new platform that combines a form of CRISPR, which allows researchers to turn individual genes on and off — which Kampmann had a significant hand in — with readouts of data indicating functions and states of individual microglia cells.

The research focuses on microglia, cells that stabilize the brain by clearing damaged neurons and the protein plaques often associated with dementia and other brain diseases. Image is in the public domain

Through this analysis, Kampmann and his team identified genes that affect the cell’s ability to survive and proliferate, how actively a cell produces inflammatory substances, and how aggressively a cell prunes synapses.

And because the scientists had identified which genes control those activities, they were able to reset the genes and return the diseased cell to a healthy state.

Armed with this new technique, Kampmann plans to explore how to control the relevant states of microglia, targeting the cells with existing pharmaceutical molecules and testing them in preclinical models. He hopes to find specific molecules that act on the genes needed to make diseased cells healthy again.

Kampmann said that once the right genes are flipped, it’s likely the “repaired” microglia will resume their responsibilities, clearing plaques associated with neurodegenerative diseases and protecting synapses rather than tearing them apart.

“Our study provides a blueprint for a new approach to treatment,” he said. “It’s a bit of a holy grail.”

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

Also see

This shows a brain in a light bulb and an alarm clock

Authors: Other authors include: Nina Dräger, Sydney Sattler, Olivia M. Teter, Kun Leng, Jason Hong, Giovanni Aviles, Claire D. Clelland, Lay Kodama, and Li Gan of UCSF. For other authors, see the study.

About this news about Alzheimer’s disease and gene editing research

Author: Robin Marks
Source: UCSF
Contact: Robin Marks – UCSF
Image: The image is in the public domain

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


Abstract

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

Microglia are emerging as the main drivers of neurological diseases. 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 generating 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 targeting the ‘druggable genome’. These screens revealed genes that control the survival, activation and phagocytosis of microglia, including neurodegeneration-associated genes.

A single-cell RNA sequencing screen readout revealed that these microglia adopt a spectrum of states similar to those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony stimulating factor-1 (CSF1R) inhibition.

Thus, our platform can systematically discover regulators of microglial states, enabling their functional characterization and therapeutic targeting.

The Valley Voice
The Valley Voicehttp://thevalleyvoice.org
Christopher Brito is a social media producer and trending writer for The Valley Voice, with a focus on sports and stories related to race and culture.

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