MIT neuroscientists have made a breakthrough in the treatment of Alzheimer’s disease by blocking an enzyme that is overactive in the brains of Alzheimer’s patients.
The researchers found that treating mice with a peptide that blocks the hyperactive version of an enzyme called CDK5 led to big reductions in neurodegeneration and DNA damage in the brain.
These mice also showed improvements in their ability to perform tasks, such as learning to navigate a water maze.
The researchers hope that the peptide could eventually be used as a treatment for patients with Alzheimer’s disease and other forms of dementia.
CDK5 is activated by a protein called P35, which is cleaved into a smaller protein called P25 in Alzheimer’s and other neurodegenerative diseases.
When bound to P25, CDK5 becomes more active in cells and allows CDK5 to phosphorylate molecules other than its usual targets, including the Tau protein.
Hyperphosphorylated Tau proteins form the neurofibrillary tangles that are one of the characteristic features of Alzheimer’s disease.
Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs tend to cause side effects because they also interfere with other cyclin-dependent kinases, so none of them have been tested in patients.
The MIT team decided to take a different approach to target P25, by using a peptide instead of a small molecule.
They designed their peptide with a sequence identical to that of a segment of CDK5 known as the T loop, which is a structure critical to the binding of CDK5 to P25.
In tests in neurons grown in a lab dish, the researchers found that treatment with the peptide led to a moderate reduction in CDK5 activity.
Those tests also showed that the peptide does not inhibit the normal CDK5-P35 complex, nor does it affect other cyclin-dependent kinases.
When the researchers tested the peptide in a mouse model of Alzheimer’s disease that has hyperactive CDK5, they saw a myriad of beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss.
These effects were much more pronounced in the mouse studies than in tests in cultured cells.
The researchers injected the peptide into mice and found that it was able to cross the blood-brain barrier and reach neurons of the hippocampus and other parts of the brain.
The peptide treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein that leads to neurofibrillary tangles.
After treatment, those mice showed reductions in both Tau pathologies and neuron loss. Along with those effects in the brain, the researchers also observed behavioral improvements.
Mice treated with the peptide performed much better in a task that required learning to navigate a water maze, which relies on spatial memory, than mice that were treated with a control peptide (a scrambled version of the peptide used to inhibit CDK5-P25).
The researchers also analyzed the changes in gene expression that occur in mouse neurons following treatment with the peptide.
Among the changes they observed was an increase in expression of about 20 genes that are typically activated by a family of gene regulators called MEF2.
While the peptide has not yet been tested in human trials, the results from the mouse studies are promising. Alzheimer’s disease is the most common form of dementia, affecting millions of people worldwide.
Current treatments can only temporarily alleviate some symptoms of the disease, and there is no cure.
The discovery of a potential treatment that can reverse neurodegeneration and other symptoms of Alzheimer’s disease could advance the outcomes of people with Alzheimer’s disease.
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The study was conducted by Ping-Chieh Pao et al and published in the Proceedings of the National Academy of Sciences.
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