A genetic mutation linked toAlzheimer’s alters a signaling pathway in some immune cells of individuals affected by the disease. To declare it in a research, are the scientists of the Weill Cornell Medicine.
The panel also found that blocking the route, with a drug currently being tested in cancer clinical trials, protects against many features of Alzheimer’s disease observed in a preclinical model. The findings could lead to new strategies to block the development of the disease or slow its progression.
The study was published on 1 December 2021 in the scientific journal Science Translational Medicines.
Immune Cells in the Brain: Here Are Which To Target and Why
Research by Weill Cornell Medicine scientists focused on microglia, the immune cells of the central nervous system that are the first to respond when something goes wrong in the brain.
Studies have identified many genetic variants linked to Alzheimer’s disease that are overexpressed in microglia., which provides compelling evidence that changes within these cells may play a role in the onset and progression of the disease.
“Microglia are guardians of the brain in healthy conditions, but they can prove harmful in disease conditions. Our goal is to identify how they become toxic and contribute to Alzheimer’s pathogenesis and whether we can identify immunomodulators to reverse toxicity without diminishing their normal protective function.Said the senior author Dr. Li Gan, director of the Alzheimer’s Disease Research Institute Helen e Robert Appel and Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
Alzheimer’s disease is the most prevalent neurodegenerative disease in aging, affecting approximately 46 million people worldwide.
The theories point to a number of potential causes, including age-related changes in the brain, along with genetic, environmental, and lifestyle factors. These lead to the accumulation of toxic proteins in the brain and, according to recent evidence, to changes in the immune system that result in the loss of neurons and their connections.
To examine how immune cells in the brain can contribute to Alzheimer’s disease, Dr. Gan and her colleagues first established the molecular footprint of microglia, immune cells of the nervous system, individual in the brain of patients with Alzheimer’s disease which carry a mutation in the gene TREM2 which greatly increases the individual’s risk of developing Alzheimer’s disease.
TREM2 it is a receptor mainly expressed by microglia in the brain and, among other functions, signals through an enzyme called AKT to modulate inflammation and metabolism.
The research team then established a mouse model by combining two strains: one that carries the AD-linked mutation in the TREM2 gene and another that shows Tau aggregates, one of the main pathological signs in the Alzheimer’s brain.
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 mice, inhibition of 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.
Importantly, as 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.
“We have identified a small molecule compound that has been tested on cancer patients, easily enters the brain, potently modulates brain immune responses, and protects against synaptic loss in animal models of Alzheimer’s disease.“Said Dr. Gan. “Our findings support further studies on this compound as a potential Alzheimer’s therapy.”
“Dementia” is an umbrella term for a range of conditions, with a variety of causes, the most common of which is Alzheimer’s disease, accounting for 60-80% of cases. It usually begins with memory loss and a mild loss of cognitive functioning, but sadly, in its chronic course, those affected lose the ability to fend for themselves and most of them need 24-hour specialist care long before death occurs.
Alzheimer’s disease predominantly affects elderly individuals: According to some estimates, 1.7% of people between the ages of 65 and 69 have dementia and the risk of developing it doubles every five years.
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