Boosting Brain Immune Cells Shows Promise in Alzheimer’s Research

In a preclinical study, researchers found that boosting angiotensin-converting enzyme (ACE) in microglia improved the immune cells’ function in clearing amyloid plaque and slowed memory and neuron loss.  

“The discovery could presage novel approaches to treating not only Alzheimer’s but also other diseases in which microglia are thought to play a role in disease pathogenesis,” said lead author Warren Tourtellotte, MD, PhD, vice chair of Pathology and Laboratory Medicine.  

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Can We Supercharge the Microglia?

Microglia attempt to remove amyloid proteins from the brain before and after the proteins aggregate and cause neurodegeneration, but the chronic activation of microglia can reduce their ability to clear amyloid and lead to immunometabolic deficiency.

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The primary role of ACE is blood pressure regulation. However, investigations by Kenneth Bernstein, MD, director of Research Education Programs in the Research Division of Immunology at Cedars-Sinai, found that expressing ACE in macrophages increased their immune function and metabolism.

We think ACE is potentially a therapeutic molecule.

To build on this work, and test this approach as a defense against Alzheimer’s, Tourtellotte and team developed a mouse model that expresses ACE in the microglia.

“The results confirmed that ACE expression in microglia not only decreases the amyloid burden and increases the microglia’s ability to process the amyloid, but also rescues neuron loss, slowing the reduction in learning and memory behavior,” said Tourtellotte.

Using single-cell sequencing to identify genes that are differentially regulated when ACE is expressed in microglia, the investigators confirmed that ACE enhances metabolic pathways known to be involved in processing amyloid.

“We think ACE is potentially a therapeutic molecule,” said Tourtellotte, “either on its own or as a cotherapy to enhance antibody therapies that have been approved by the U.S. Food and Drug Administration and are currently in use but are not as effective as people had hoped.”

The team is now engineering human stem cells into ACE-expressing microglia to prove their potential efficacy in human subjects.

“Our long-term goal is a clinical trial in which we test the utility of supercharged microglia to clear amyloid in patients with Alzheimer’s,” Tourtellotte said.