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Alzheimer’s: Scientists find way to switch some diseased cells back to a healthy state
Written by Deep Shukla on August 19, 2022 — Fact checked by Alexandra Sanfins, Ph.D.
Microglia are thought to be key drivers of many neurological conditions, including Alzheimer’s disease. Roxana Wegner/Getty Images
Evidence suggests that microglia—the primary immune cells in the brain—may directly contribute to the development of neurodegenerative conditions such as Alzheimer’s disease (AD).
Due to technical challenges, scientists have not been able to decipher the molecular mechanisms underlying microglia activity or function in healthy and diseased brains.
Scientists have now developed a new method based on the gene-editing tool CRISPR to identify genes that modulate the function of microglia.
By identifying the genes involved in disease-driving states of microglial activity, scientists were able to switch the genes on and off, paving the path for developing new therapies for AD.
In a recent study published inNature NeuroscienceTrusted Source, scientists revealed a novel screening platform for characterizing genes that regulate specific microglialTrusted Source functions which may contribute to Alzheimer’s disease (AD).
Characterizing regulatory genes that cause microglia to switch from a healthy state to a diseased state, such as in the brains of individuals with AD and other neurodegenerative conditions, could help develop therapeutics that target these genes or the proteins encoded by these genes.
“Since microglia are guardians of the brain’s homeostasis, it is important to identify specific drivers that lead to neuronal toxicity for therapeutic intervention. Our new CRISPR screening platform […] enables us to identify these drivers in a rapid, scalable manner. We already uncovered druggable targets that control microglia states, and the next steps would be to test these in relevant preclinical models.”
— Dr. Li Gan, study co-author and neuroscientist at the Weill Cornell Medical College, speaking to Medical News Today
The role of microglia
AD is the most common form of dementia, accounting for 60-80% of all dementia cases. Despite the advances in the understanding of AD, there is a lack of effective treatments for this neurodegenerative disease.
The accumulation of the misfolded beta-amyloidTrusted Source protein into clumps or plaques is one of the hallmarks of AD. A considerable amount of research has focused on mutations that lead to the abnormal processing of the beta-amyloid protein and, subsequently, its accumulation.
However, treatments targeting the pathways involved in the processing of beta-amyloid have not been successful.
Moreover, researchers have found that individuals with AD often do not showTrusted Source mutations in genes associated with the accumulation of the amyloid protein. In contrast, recent evidence suggests that individuals with AD often show deficits in the clearanceTrusted Source or removal of misfolded beta-amyloid.
This may be due to the dysfunction of microglia, which are the primary immune cells in the brain. One of the functions of microglia includes phagocytosis—a process involving the ingestion of dead cells, pathogens, and misfolded proteins to facilitate their removal.
There is growing evidence that the abilityTrusted Source of microglia to remove the beta-amyloid protein may be impaired in AD. Microglia may also contribute to the development of AD by secreting inflammatory proteins and causing excessive removal of neurons and synapsesTrusted Source, the links between neurons that allow them to “communicate.”
In addition to AD, there is evidence suggesting that microglia may also contributeTrusted Source to the development of other neurodegenerative disorders.
However, the molecular mechanisms underlying the wide array of functions performed by microglia in normal conditions and diseases such as AD are not well understood.
How CRISPR technology can help
Functional genetic screening is a tool used for identifying genes that are involved in a specific cellular function. Such screens involve the inhibition or activation of a specific gene in a cell to assess whether the change in expression levels of that gene impacts a certain function of interest, such as cell proliferation.
In recent years, researchers have adapted the gene-editing tool known as CRISPR-Cas9 to identify genes involved in various diseases, including cancer. The advantages of the CRISPR screening platform include its higher sensitivity and greater reproducibility than previously used screening methods.
CRISPR-Cas9 consists of a small piece of RNA called a guide sequence and the enzyme Cas9. The guide RNA binds to the DNA region of interest, allowing Cas9 to bind and cleave the DNA at the targeted site.
In the present study, the researchers used a modified CRISPR-Cas9 system involving a deactivated Cas9 (dCas9) enzyme that does not cleave the DNA. Besides the deactivated Cas9 enzyme, the modified CRISPR-dCas9 platform also consists of proteins that can either upregulate or downregulate the gene of interest—or in other words, turn them on and off.
Such CRISPR screens involve the delivery of the guide RNA to the cell with the help of a genetically engineered virus— a viral vectorTrusted Source. However, using viruses to deliver the guide RNA to mature microglia has been challenging
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