MDM2 Inhibition Reduces Loss of Synapses in a Cell Culture Model

Loss of synaptic connections between neurons is one of the harmful outcomes of neurodegenerative conditions such as Alzheimer's disease. In mouse models of Alzheimer's disease engineered to produce amyloid-β, excessive pruning of synapses is thought to be a maladaptive response to the presence of misfolded amyloid-β. Investigating the details of this excessive pruning in cell cultures, researchers have found a way to interfere in the signaling involved. At least in vitro there are positive results, but it remains to be seen as to how well this approach will work in the animal models of Alzheimer's disease.

Researchers, using rodent neurons, found that targeting a protein called Mdm2 with an experimental cancer drug known as nutlin, stopped neurotoxic amyloid-b peptides that accumulate in Alzheimer's disease (AD) from overly pruning synapses. Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. Trimming excess dendritic spine synapses is normal in the post-natal brain but can be abnormally accelerated in AD, causing loss of memory and learning.

When this protein Mdm2 is turned on inappropriately, it leads to pruning of the synapses when amyloid-b is present. Amyloid-b is the main component of amyloid plaques found in the brain of those with AD. "When we used the drug that inhibits Mdm2 on the neurons, it completely blocked dendritic spine loss triggered by amyloid-b. So inhibiting this protein is clearly working. There are questions if anti-amyloid therapy is the be-all and end-all of AD therapy. 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."


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