Caspase-1 inhibition reverses Alzheimer pathology in mice!

Caspase-1 inhibition reverses Alzheimer pathology in mice!

New research reveals that a novel drug reverses memory deficits and stops Alzheimer disease pathology (AD) in an animal model. Importantly, this drug has already proven to be non-toxic for humans in a clinical setting and could, therefore, be brought quickly to trials in humans against AD. These findings are published in Nature Communications.

The team discovered that the Caspase-6 enzyme is highly activated in Alzheimer disease brain lesions and associated with loss of memory. So, they pursued the hypothesis that stopping Caspase-6 might provide relief from memory loss and stop progressive dementia. Since there are no specific Caspase-6 inhibitors, the team moved upstream, ultimately discovering that Caspase-1 was responsible for activating Caspase-6.

"This was a significant revelation because Caspase-1 inhibitors had been developed for treating inflammatory diseases," explains the senior author. "Thus, we decided to test the effects of a particular Caspase-1 inhibitor, called VX-765, against memory loss and brain pathologies in a mouse model of Alzheimer disease."

Authors show that small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD. Cessation of VX-765 results in the reappearance of memory deficits in the mice after 1 month and recommencement of treatment re-establishes normal cognition.

VX-765 prevents progressive amyloid beta peptide deposition, reverses brain inflammation, and normalizes synaptophysin protein levels in mouse hippocampus. Consistent with these findings, Caspase-1 null J20 mice are protected from episodic and spatial memory deficits, neuroinflammation and Aβ accumulation.
 
The work showed that VX-765 has an unprecedented beneficial effect in Alzheimer mice. In addition to being safe for humans at relatively high doses for extended periods of time, it is capable of reaching the brain, a significant challenge in the development of drugs against disorders of the brain.

While the senior author cautions that there is a considerable bridge to cross between the mouse brain and that of a human, but believes that since the work has first identified the Caspase-1/Caspase-6 neurodegenerative pathway in human neurons and in human Alzheimer brains, there is a chance that this drug will work just as well in humans as it did in mice. Nevertheless, a clinical trial is needed to determine whether the drug will be beneficial against Alzheimer disease in humans.

https://www.nature.com/articles/s41467-018-06449-x

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