Role of Key protein in Progression of Alzheimer’s Disease

Researchers Found Inhibiting Key Protein May Stop Alzheimer’s Progression
Study: Amyloid-β-induced dendritic spine elimination requires Ca2+-permeable AMPA receptors, AKAP-Calcineurin-NFAT signaling, and the NFAT target gene Mdm2.

Researchers at the University of Colorado Anschutz Medical Campus discovered that blocking a key protein can prevent the breakdown of synapses and dendritic spines seen in Alzheimer’s disease (AD). Tyler Martinez, a PhD student in pharmacology and molecular medicine at the University of Colorado School of Medicine, is the first author of the study, which was published this week in the journal eNeuro.

Using mouse neurons, the researchers discovered that targeting a protein called Mdm2 with an experimental cancer treatment called nutlin prevented neurotoxic amyloid-b peptides, which accumulate in Alzheimer’s disease, from overly pruning synapses.

“Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus,” stated the study’s main author, Professor Mark Dell’Acqua, PhD, vice-chair of the Department of Pharmacology at the University of Colorado School of Medicine.

According to Dell’Acqua, cutting extra dendritic spine synapses is normal in the postnatal brain, but it can be accelerated in Alzheimer’s disease, resulting in memory and learning loss.

“When this protein Mdm2 is turned on inappropriately, it leads to pruning of the synapses when amyloid-b is present,” he said. Amyloid-b is the primary component of amyloid plaques detected in the brains of people with Alzheimer’s disease. “We utilized a medication that inhibits Mdm2 on neurons, and it totally stopped dendritic spine loss caused by amyloid-b. Inhibiting this protein is definitely effective.”

An ‘encouraging’ initial step

Dendritic spines sprout from dendrites, which are neuronal components that receive synaptic signals important for learning and memory.

Dell’Acqua, head of the CU School of Medicine’s NeuroTechnology Center, observed that much of the research into Alzheimer’s disease therapeutics focuses on removing amyloid plaques from the brain.

“There are questions if anti-amyloid therapy is the be-all and end-all of AD therapy,” he added. “Even if you could tolerate the high cost, the effectiveness is questionable. We are saying that it may also be possible to intervene in the process by blocking some of the impacts of amyloid-B. And you could intervene by targeting Mdm2.”

The next step is to see if they can prevent AD progression in an animal model. If that’s the case, human trials may take place in the future. Drugs targeting Mdm2 for cancer are already in development and clinical trials, but they must be approved by the Food and Drug Administration.

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

More information: Tyler P. Martinez et al, Amyloid-β-induced dendritic spine elimination requires Ca2+-permeable AMPA receptors, AKAP-Calcineurin-NFAT signaling, and the NFAT target gene Mdm2, eNeuro (2024). DOI: 10.1523/ENEURO.0175-23.2024

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