Blocking a key protein could halt the progression of Alzheimer’s disease

Researchers at the University of Colorado Anschutz Medical Campus have found that inhibiting a key protein can stop the destruction of synapses and dendritic spines commonly seen in Alzheimer’s disease.

The study, whose first author is Tyler Martinez, a doctoral student in pharmacology and molecular medicine. program at the University of Colorado School of Medicine, was recently published in the journal in Euro.

The researchers, using rodent neurons, found that targeting a protein called Mdm2 with an experimental cancer drug known as Nutlin stopped the neurotoxic amyloid-β peptides that accumulate in Alzheimer’s disease ( MA) from excessive pruning of synapses.

“Cognitive impairments associated with AD correlate with dendritic spine and loss of excitatory synapses, particularly in the hippocampus,” said Professor Mark Dell’Acqua, Ph.D., lead author of the study. , vice chair of the Department of Pharmacology at the CU School of Medicine.

Dell’Acqua said the cutting of excess dendritic synapses from the spine is normal in the postnatal brain, but can be abnormally accelerated in AD, leading to loss of memory and learning.

“When this Mdm2 protein is inappropriately activated, it leads to synapse pruning when amyloid-β is present,” he said. Amyloid-β is the main component of amyloid plaques found in the brains of people with AD. “When we used the drug that inhibits Mdm2 on neurons, it completely blocked the loss of the dendritic spine triggered by amyloid-β. So inhibiting this protein clearly works.”

Dendritic spines protrude from dendrites, a component of neurons, and receive synaptic signals essential for learning and memory.

Dell’Acqua, director of the Neurotechnology Center at the University of California School of Medicine, noted that much of the research on AD therapies tends to focus on eradicating amyloid plaques in the brain.

“It is questionable whether anti-amyloid therapy is the ultimate solution to the treatment of AD,” he said. “Even if you could tolerate the high cost, the effectiveness is questionable. We say it might also be possible to intervene in the process by blocking some of the impacts of amyloid-β. And you could intervene by targeting Mdm2 .”

The next step is to determine whether they can block the progression of Alzheimer’s disease in an animal model. If so, human trials could take place in the future. Drugs targeting Mdm2 are already being developed and in clinical trials for cancer, but have yet to be approved by the FDA.

“This is an encouraging first step that gives us a new avenue to pursue,” Dell’Acqua said.