Enhanced Immune Cells Resist Alzheimer's, Preserve Cognition in Mice

A recent study led by Cedars-Sinai neuroscientists provides insight into how altered immune cells potentially could be used to help preserve cognition in patients with Alzheimer's disease.

Investigators genetically modified immune cells called monocytes, which travel through the bloodstream to respond to tissue damage or inflammation. When administered to laboratory mice that exhibit features of Alzheimer's disease, these modified immune cells effectively targeted and destroyed protein fragments associated with the disease.

"This research is a critical step toward testing similar immune strategies in humans," said Maya Koronyo-Hamaoui, PhD, associate professor of neurosurgery and biomedical sciences at Cedars-Sinai, who led the investigation.

Alzheimer's disease is the leading cause of dementia, which is characterized by loss of memory and decline in cognitive function.

Although scientists don't know exactly what causes it, Alzheimer's is strongly linked with the buildup of toxic forms of amyloid beta proteins at the synapses of neurons—the points where neurons communicate with each other.

Koronyo-Hamaoui cautioned that several more phases of research, including successful human clinical trials, would need to be completed before treatments might become available to patients. These treatments, if found to be safe and effective in humans, could provide what clinicians call disease-modifying therapy—that is, therapy that slows disease progression.

In the experiments led by Koronyo-Hamaoui, in collaboration with Kenneth E. Bernstein, MD, the investigators genetically enhanced monocytes to produce more of a substance, called angiotensin-converting enzyme (ACE), that degrades amyloid beta.

"The alterations we made produced super monocytes that could infiltrate into the brain in larger numbers—almost three-fold higher numbers—so they were capable of increasing their availability to injured brain tissue," Koronyo-Hamaoui said.

Researchers then tested two methods of transferring these ACE-enhanced immune cells into laboratory mice with Alzheimer's-like disease, either by bone marrow transplantation or blood transfusion. A third control group either received unmodified immune cells or saline.

The study, published in Brain, a journal of Oxford University Press, found that in both the mice that received bone marrow transplants and in those that received blood transfusion, the ACE-enhanced monocytes were better than standard monocytes at breaking up even the most toxic amyloid beta proteins.

Critically, the study also showed that the enhanced monocytes reduced inflammation in the brain and secreted more of a certain substance, insulin-like growth factor 1, which is important for survival of neurons and the production of new synapses between them.

While previous studies have demonstrated the ability of immune cells to clear amyloid beta from the brain, this is the first study to show the precise role of ACE-enhanced blood monocytes in removing amyloid beta, regulating brain inflammation and promoting regeneration, Koronyo-Hamaoui said.

"This is one area where we believe the outcome was increased synaptic density and improved cognition," she explained.

As the American population ages and as advances in medicine allow people to live longer, concern about Alzheimer's disease is growing, and the search for treatments is expanding. According to the federal Centers for Disease Control and Prevention, the number of Americans living with Alzheimer's disease is projected to triple to nearly 14 million by 2060.

The research was supported by the National Institute on Aging of the National Institutes of Health under awards numbers R01 AG055865 and R01 AG042195, BrightFocus Foundation, The Coins for Alzheimer's Research Trust – CART Fund, The Saban Foundation and The Marciano Foundation.

Citation: Brain, "Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease," published online December 3, 2019. DOI: https://doi.org/10.1093/brain/awz364.

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