Taking Out The Trash: Boosting Garbage Disposal In The Brain May Halt Dementia

Alzheimer's disease is associated with a toxic build up within the brain, but drugs enhancing cell 'garbage disposal' mechanisms may slow its progression.

Improving waste management

New neuroscience research suggests that a discontinued depression drug Rolipram can boost proteasome activity - an organelle responsible for dealing with old or damaged proteins. 

"We have shown for the first time that it's possible to use a drug to activate this disposal system in neurons and effectively slow down disease," said lead researcher Karen E. Duff. "This has the potential to open up new avenues of treatment for Alzheimer's and many other neurodegenerative diseases"

Recycling and waste disposal are key cellular processes

Cells have two main 'machines' that recycle and destroy damaged and old material: the proteasome and the lysosome. The proteasome is specific to proteins and cleaves them into small peptide molecules, and the lysosome deals with many different types of molecules, breaking them down to single amino acids. If a cell wants to degrade a particular protein, it can attach something called a ubiquitin tag to it, which targets it to the proteasome. This specific label identifies proteins for disposal. 

While cells naturally clear themselves out, a problem in this process is implicated in both Alzheimer's and aging itself. In Alzheimer's disease, sticky molecules like amyloid beta or tau can inhibit this disposal process and make removal extremely challenging. Researchers hypothesized that giving the process a helping hand might reduce the load, and help combat the disease. 

Can targeting the proteasome ease the burden in Alzheimer's?

In a mouse model, tau proteins associated with Alzheimer's progression were found to stick to the proteasome and inhibit its ability to do its job. Applying the drug Rolipram in these mice had a re-activation effect on the proteasome - restoring normal function and improving memory. 

Rolipram works by inhibiting an enzyme called PDE-4 and somehow manages to increase disposal of this excess of tau proteins. 

Credit: Karen Duff/Columbia University Medical Centre

"We still don't know exactly where the activation is happening, but what's new is that we can modify the proteasome to increase its activity. There could be many other ways to do this"

While Rolipram has undesirable side effects itself, the concept of boosting innate disposal processes is promising. Developing additional, safe drugs to target and strengthen these disposal mechanisms could be a potent way of delaying neurodegenerative conditions in the future. 

Watch a summary of the research below:

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