Inhibition of key proteins can reverse neuronal loss and slow its progression

Researchers have identified a key protein called murine double minute 2 (Mdm2) whose inhibition can significantly slow the progression of Alzheimer’s. By targeting the protein with nutlin, a combination of an experimental drug commonly used against cancer, the excessive loss of synapses and dendritic spines inherent in the disease can be curbed. This may represent a new therapeutic approach that is potentially more effective than traditional strategies that directly target amyloid proteins.

Although Alzheimer’s is the most prevalent neurodegenerative disease in the world, its etiology remains one of the greatest mysteries in neuroscience today. Indeed, more than three decades of research have suggested that it is primarily due to the accumulation of amyloid plaques in neurons (the amyloid cascade hypothesis). However, therapeutic strategies that directly target these proteins are usually not effective enough to alleviate disease symptoms.

Consequently, the hypothesis based on beta-amyloid protein has recently been called into question. Research has suggested the involvement of various factors, such as, for example, gut microbiota, viral infections, or the presence of short toxic RNA strands. Lifestyle and environmental factors, such as diet and air pollution, have also been suggested. However, the proposed hypotheses are so heterogeneous that there is still no consensus on the true pathophysiological mechanisms of the disease.

The researchers then wondered whether studying the signaling downstream of protein accumulation might lead to more effective therapeutic strategies. ”
It is questionable whether anti-amyloid therapy is the ultimate solution for the treatment of AD. Even if the high cost can be tolerated, the effectiveness is questionable “, explains Mark Dell’Acqua, vice chair of the Department of Pharmacology at the University of Colorado School of Medicine, in a press release.

Studies in mouse models have specifically shown that the soluble form of beta-amyloid protein impairs learning and memory by inducing excessive pruning of synapses and dendritic spines in the hippocampus (resulting in Finally for loss of neurons). Dendritic spines are small outgrowths on the dendrites of certain neurons and play an essential role in synaptic transmission and neuronal plasticity.

While this pruning process naturally begins in our brains shortly after birth, it is abnormally accelerated in Alzheimer’s disease. ” Cognitive impairments associated with Alzheimer’s disease are associated with pruning of dendritic spines and loss of excitatory synapses, particularly in the hippocampus. “, explains Dell’Acqua. As part of a new study published in the journal in eurosDell’Acqua and his team then explored the postsynaptic signaling mechanisms (mediated by beta-amyloid protein) that regulate this damage.

A protein that induces excessive loss of synapses

In one experiment, experts in the new study identified a transcriptional target called E3-ubiquitin ligase, or Mdm2, that is involved in the pruning of dendritic spines and synapses. To study the mechanism, they isolated neuronal cells from the hippocampi of a mouse model of Alzheimer’s.

They found that MDM2 was abnormally activated upstream by a signaling pathway mediated by amyloid beta protein and controlled by a protein called AKAP150. The latter is required to maintain synapse formation and is activated by calcium ion influx. ” When this Mdm2 protein is inappropriately activated, it leads to pruning of synapses when beta-amyloid is present. “, explains Dell’Acqua.

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To confirm these observations, the researchers treated mouse neurons with nutlin, an experimental anticancer drug that specifically inhibits Mdm2. They found that the molecule successfully overcame beta-amyloid-induced pruning of dendritic spines and synapses.

Although these results are still preliminary, experts believe they could lead to a potentially more effective therapeutic strategy than results based directly on the beta-amyloid protein. The next step is to repeat in vivo Experiments to confirm whether Nutlin can actually slow disease progression and relieve symptoms. In addition, the drug is currently the subject of clinical trials for cancer, which may provide valuable information regarding its mode of action and safety.

Source: eNeuro