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Scientists at the Weill Cornell Research Institute of Medicine have discovered that a genetic mutation linked to Alzheimer’s disease alters a signaling pathway in certain immune cells of people with the disease. However, tests in mice have shown that blocking this pathway, using an experimental drug currently being tested against cancer, appears to slow or even stop the development of the disease. It is a new hope of treatment for this disease that affects millions of people around the world.
The immune cells in question form what is called microglia; The macrophages of the central nervous system are the main line of immune defense against pathogens. Several previous studies have identified many genetic mutations related to Alzheimer’s disease that are highly expressed in microglia; therefore, it is highly likely that changes in these cells influence the onset and progression of the disease.
“Microglia are the guardian of the brain in healthy conditions, but it can become harmful with disease. Our goal is to identify how these cells become toxic and contribute to the pathogenesis of Alzheimer’s disease, ”explains Dr. Li Gan, neurodegenerative disease specialist at Weill Cornell Medicine. She and her team set out to identify immunomodulators that can reverse the toxicity of microglia cells without reducing their normal protective function.
A treatment based on the inhibition of an enzyme.
Alzheimer’s disease is the most common neurodegenerative disease in the elderly; It affects about 46 million people worldwide, including nearly 1.2 million in France. According to the Ministry of Solidarity and Health, the disease affects 23% of the population after 80 years. The precise causes of the disease are not yet clearly identified; However, theories suggest that genetic, environmental and lifestyle factors play an important role in the onset of the disease, as do age-related brain changes.
These last years of research have allowed a better understanding of the mechanisms involved: the accumulation of toxic proteins in the brain (β-amyloid peptides and the Tau protein), as well as changes in the immune system (highlighted in recent studies), lead to degradation and loss of neurons and their connections, leading to progressive loss of memory and certain cognitive functions.
To better understand how immune cells in the brain contribute to Alzheimer’s disease, Dr. Gan and his colleagues first established the molecular footprint of each microglial cell in the brains of patients with a mutation in the gene. TREM2, a mutation known to be associated with a dramatically increased risk of developing the disease. This particular mutation of the TREM2 gene, R47H noted, nearly triples the risk of developing Alzheimer’s disease, according to a study published in 2013.
TREM2 (myeloid cell-expressed activation receptor 2) is a receptor expressed primarily by microglia in the brain; Among other functions, it sends signals to modulate inflammation and metabolism through an enzyme called AKT. However, an experiment carried out in mouse models of Alzheimer’s showed that the inhibition of this enzyme allowed to reverse the inflammation of the microglia and, therefore, to protect the neurons of the brain.
Neurons protected against synaptic toxicity
The team established their mouse model by combining two strains: one carried the R47H mutation and the other exhibited aggregates of the Tau protein, one of the main pathological features of a brain with Alzheimer’s disease. Mouse models carrying the mutation had memory-related deficits (as did human patients); More specifically, the R47H mutation “induced and exacerbated Tau-mediated spatial memory deficits in female mice,” the researchers write. Furthermore, their microglia expressed high levels of pro-inflammatory cytokines and exhibited an overactive AKT signaling pathway.
Single-cell sequencing of the microglial response in a mouse model of Alzheimer’s disease. Each point represents a microglial cell and the different colors represent the different microglial states. Treatment with the investigational drug MK-2206 (right) killed a subset of disease-associated microglial cells (marked in pink) and protected against synaptic loss. © F. Sayed et al.
Therefore, the researchers tried to inhibit AKT in mice, using a drug called MK-2206. It turns out that this treatment is currently being tested in several cancer clinical trials. In fact, AKT signaling also contributes to the pathogenesis of many types of cancer; Therefore, the safety of this treatment is already the subject of a study. The team found that MK-2206 reversed inflammatory processes in microglia and even protected neurons against the synaptic toxicity characteristic of the disease.
The demonstration of the mechanisms of the R47H mutation that promote Alzheimer’s disease confirms that inhibitors of AKT signaling constitute a relevant microglial modulation strategy to treat the disease. “Our results support the continuation of the study of [MK-2206] as a potential therapy for Alzheimer’s disease, ”concludes Dr. Gan.
F. Sayed et al.
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