Targeting the Brain’s Immune Cells Could Prevent or Treat Alzheimer’s Disease

A gene mutation linked to Alzheimer’s disease alters a signaling pathway in certain immune cells of individuals with the disease, according to a new study by scientists at Weill Cornell Medicine. 

The study focused on microglia, immune cells of the central nervous system that are the first to respond when something goes wrong in the brain.

“Microglia are guardians of the brain under healthy conditions, but can turn detrimental in disease conditions. Our goal is to identify how they become toxic and contribute to Alzheimer’s disease pathogenesis and whether we can identify immune modulators to reverse the toxicity without diminishing their normal protective function,” said senior author Dr. Li Gan.

Alzheimer’s disease is the most prevalent neurodegenerative disease in aging, affecting approximately 46 million people worldwide.

Theories point to a number of potential causes, including age-related changes in the brain, along with genetic, environmental, and lifestyle factors.

To examine how the brain’s immune cells may contribute to Alzheimer’s disease, Dr. Gan and her colleagues first established the molecule fingerprint of individual microglia in the brains of patients with Alzheimer’s disease who carry a mutation in the TREM2 gene that markedly elevates individual’s risk for developing Alzheimer’s disease.

TREM2 is a receptor mainly expressed by microglia in the brain, and among other functions, it signals through an enzyme named AKT to modulate inflammation and metabolism.

The team then established a mouse model by combining two strains; one that carries the AD-linked mutation in the TREM2 gene and another that exhibits Tau aggregates, one of the major pathological hallmarks in Alzheimer brains.

Both patients and mice with the mutation demonstrated memory-related deficits, and their microglia expressed high levels of inflammatory molecules and exhibited an overactive AKT signaling pathway.

In the mice, inhibiting AKT with a drug called MK-2206 reversed the inflammatory properties of microglia and protected against synaptic toxicity — a type of damage to the brain’s neurons that is a hallmark of Alzheimer’s disease.

Importantly, because AKT signaling also contributes to the pathogenesis of many types of cancer, MK-2206 is currently being evaluated in multiple cancer clinical trials.

Therefore, the safety of the drug is already under investigation.

“Our findings support further study of this compound as a potential therapy for Alzheimer’s disease.”

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Sources:

Faten A. Sayed, Lay Kodama, Li Fan, Gillian K. Carling, Joe C. Udeochu, David Le, Qingyun Li, Lu Zhou, Man Ying Wong, Rose Horowitz, Pearly Ye, Hansruedi Mathys, Minghui Wang, Xiang Niu, Linas Mazutis, Xueqiao Jiang, Xueting Wang, Fuying Gao, Matthew Brendel, Maria Telpoukhovskaia, Tara E. Tracy, Georgia Frost, Yungui Zhou, Yaqiao Li, Yue Qiu, Zuolin Cheng, Guoqiang Yu, John Hardy, Giovanni Coppola, Fei Wang, Michael A. DeTure, Bin Zhang, Lei Xie, John Q. Trajnowski, Virginia M. Y. Lee, Shiaoching Gong, Subhash C. Sinha, Dennis W. Dickson, Wenjie Luo, Li Gan. AD-linked R47H- TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Science Translational Medicine, 2021; 13 (622) DOI: 10.1126/scitranslmed.abe3947

Weill Cornell Medicine. “Targeting the brain’s immune cells may help prevent or treat Alzheimer’s disease.” ScienceDaily. ScienceDaily, 1 December 2021. <www.sciencedaily.com/releases/2021/12/211201145309.htm>.

Materials provided by Weill Cornell Medicine. Note: Content may be edited for style and length.

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