A new study has successfully reversed both the biological and behavioral hallmarks of Alzheimer's disease in mouse models. The research found that slowly depleting the presence of a certain enzyme can reverse the formation of amyloid plaques in the brain. Illustrating the tricky path current Alzheimer's research faces, the study was published literally hours after giant pharmaceutical company Merck announced the cancellation of a Phase 3 clinical trial surrounding a drug that targets the exact same enzyme.
The new study from a team at the Cleveland Clinic Lerner Research Institute focused on an enzyme called BACE1 (aka beta-secretase), which is known to contribute to the formation of the toxic amyloid proteins that congregate as plaques on the brain, and are hypothesized to be the source of most Alzheimer's symptoms.
Completely blocking BACE1 in previous mouse models has resulted in major brain defects, as the enzyme controls several fundamental developmental processes. So the team engineered a mouse model that gradually lost the enzyme as it grew older and then bred those mice with rodents that were engineered to develop amyloid plaques from an age of 75 days.
This allowed the researchers to simulate both the age-related progression of Alzheimer's disease, and an associated progressive reduction in BACE1 activity. The results were remarkably positive, with the reduction in BACE1 activity not only stalling the development of amyloid plaques in the mice, but actually removing the deposits that had already formed. At 10 months of age the mouse models were found have no amyloid plaque deposits at all.
"Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult," says Riqiang Yan, one of the researchers working on the study. "Our data show that BACE1 inhibitors have the potential to treat Alzheimer's disease patients without unwanted toxicity."
The results found that as well as lowering beta-amyloid peptide levels, the animals displayed improvements in both learning and memory, suggesting something akin to a reversal of Alzheimer's related symptoms. Closer inspection of neuronal activity did reveal that reducing BACE1 activity did not completely restore synaptic functions and the researchers do suggest that caution is still warranted as the enzyme does seem to be fundamental for optimal cognitive function.
Despite some compelling recent scientific breakthroughs in Alzheimer's research over the past year, several high-profile clinical trial failures have resulted in some big companies pulling back their investments in the area. Early in 2018, pharma giant Pfizer revealed it was ending all research into drugs for Alzheimer's and Parkinson's diseases. The controversial move involved several hundred layoffs and a significant reallocation of funds to other research areas.
Just hours before this latest Cleveland Clinic Lerner Research Institute study was published, another blow to the field came when Merck announced it was discontinuing a Phase 3 clinical trial into a drug called verubecestat, following a recommendation suggesting, "it was unlikely that positive benefit/risk could be established if the trial continued." This comes after years of research and clinical trials up to this point.
Another major pharma player, Roche, canceled its BACE1 research back in 2013, but several large-scale trials for BACE1 inhibitors are still currently in development or underway. The Merck Phase 3 trial failure does strike a giant blow to this once-promising field, despite this new research reiterating the pathway as effective, at least in animal models.
While some are suggesting the failure of these BACE1 trials indicate that the amyloid plaque hypothesis for Alzheimer's disease may in fact be wrong, other recent research still suggests more targeted methods of inhibiting the enzyme could result in positive outcomes. A study from the University of British Columbia last year found that specific mutations in the enzyme could be harnessed, retaining its important beneficial effects while simultaneously halting its tendency to promote amyloid protein generation.
We still may be some years away from an effective Alzheimer's disease treatment, but all is certainly not lost with many dedicated researchers still working hard to find potentially useful drug targets.
The new research was published in the Journal of Experimental Medicine.
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