Research Summary: Alzheimer’s Disease Successfully Reversed in Mice
A study recently published in the Journal of Experimental Medicine has sparked excitement for its breakthrough revelations about Alzheimer’s Disease treatment. This study, led by Riqiang Yan, is significant as being the first which shows complete reversal of amyloid plaque formation and almost complete restoration of function in mouse models of Alzheimer’s disease.
BACE1 (aka beta-secretase) is an enzyme which breaks amyloid precursor protein (APP) to produce beta-amyloid peptides. Over-accumulation of these peptides results in the formation of amyloid plaques in the brain, characterising the early stages of Alzheimer’s disease. These plaques disrupt surrounding brain tissue, resulting in disrupted brain function. BACE1 therefore makes a promising therapeutic target for treating Alzheimer’s Disease.
A problem encountered in previous research is that mice lacking BACE1 not only show reduced beta-amyloid peptide accumulation, but also results experience severe neurodevelopmental defects. This suggests that BACE1 is responsible for multiple other processes in the brain, not simply cleaving APP. Research using mice which do not express BACE1 has therefore been difficult to conduct.
Yan’s team, based at Cleveland Clinic Lerner Research Institute, found a way to solve this problem. Rather than breeding mice which lacked BACE1 entirely, they instead bred mice which would lose the enzyme gradually as they aged. This resulted in mice which developed normally and remained healthy despite the loss of BACE1 over time. These mice were then bred with mice which develop amyloid plaques at 75 days of age, resulting in offspring which also form plaques at this age while experiencing reduced BACE1 levels over time.
These hybrids’ amyloid plaques reduced over time as their BACE1 levels gradually decreased. By 10 months old, all the plaques which had initially formed were gone. Other markers of Alzheimer’s disease – such as memory loss, learning difficulties, activated microglial cells and abnormal neuronal process formation – were reversed too. However, electrophysiological recordings showed that some synaptic function remained impaired, indicating that BACE1 is possibly required for optimum synaptic function.
The reasons these results are exciting are two-fold. First, they highlight the potential of BACE1 inhibitors in treating Alzheimer’s disease. Second, they demonstrate that the damage caused by amyloid plaque formation can be almost entirely reversed. While much more work will be required before this treatment can be tested in human trials – such as reducing damage caused by inhibiting BACE1 – this study has broken new ground on which researchers can stride forward.
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