Microglia and Alzheimer's
A group of researchers from the Department of Weill Cornell Medicine at Cornell University, USA, has shown that a gene mutation associated with Alzheimer's disease alters the signaling pathway in certain immune cells, and blocking this pathway with a drug currently being tested in clinical cancer research reduces the manifestations of the disease. The results were obtained in mouse models and can be used to create a drug that stops or slows down the progression of Alzheimer's disease.
Microglia is a collection of immune cells of the central nervous system that are the first to respond to pathological processes in the brain. Studies have identified many genetic variants associated with Alzheimer's disease that are particularly pronounced in microglia, providing compelling evidence that changes in these cells may play a role in the onset and progression of the disease.
Alzheimer's disease is the most common neurodegenerative disease affecting approximately 46 million people worldwide. A number of potential causes have been identified, including age-related changes in the brain, as well as genetic, environmental and life factors that lead to the accumulation of toxic proteins in the brain and, according to recent data, changes in the immune system. Against the background of these changes, neurons die and connections between them disappear.
To study how immune brain cells can contribute to the development of Alzheimer's disease, researchers have identified a molecular fingerprint (a way to encode the structure of the molecule) of microglia in the brains of patients who carry a mutation in the TREM2 gene that significantly increases the risk of developing Alzheimer's disease. The triggering receptor expressed on myeloid cells 2 (TREM2) is a protein mainly expressed by microglia in the brain, which, among other functions, transmits signals via the enzyme protein kinase B (AKT) to modulate inflammation and metabolism.
Single-cell RNA sequenced microglia analysis of a mouse model of Alzheimer's disease. Treatment with the experimental drug MK2206 depleted the subcluster of the disease-associated microglia (pink) and protected against synapse loss. Each dot represents one microglia cell, and different colors represent different microglia states.
The team then created a mouse model with two characteristic features: an Alzheimer's-related TREM2 gene mutation and a pathological accumulation of tau protein. Both patients and mice with the mutation had memory deficits, and microglia expressed high levels of inflammatory molecules and demonstrated hyperactivity of the AKT signaling pathway. In mice, the inhibition of AKT by the experimental drug MK-2206 led to a decrease in the inflammatory activity of microglia and the preservation of synapses – nerve contacts, damage to which is a hallmark of Alzheimer's disease.
Since AKT activity is also associated with the progression of many oncological diseases, MK-2206 is currently being studied in numerous clinical cancer studies. Therefore, the safety of the drug for humans is already being tested.
The article by A.Faten et al. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation is published in the journal Science Translational Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on Weill Cornell Medicine: Targeting the Brain's Immune Cells May Help Prevent or Treat Alzheimer's Disease.