Medical News Today: Blocking enzyme 'dramatically reverses' Alzheimer's in mice

Medical News Today: Blocking enzyme 'dramatically reverses' Alzheimer's in mice
Recent research reveals that targeting an enzyme called BACE1 can "completely reverse" the buildup of beta-amyloid plaque in the brain, which is a hallmark of Alzheimer's disease. For now, the findings are limited to mice, but they provide hope that humans may one day benefit from the same treatment.
beta amyloid plaques
In Alzheimer's, beta-amyloid plaques build on and around neurons. But new research suggests that such damage may be completely reversible.

The study was carried out by scientists from the Cleveland Clinic Lerner Research Institute in Ohio.


The researchers were led by Riqiang Yan, of the Department of Neuroscience at the University of Connecticut School of Medicine in Farmington.


As Yan and colleagues explain in their paper, the enzyme in question helps to produce beta-amyloid peptide. An excessive accumulation of this peptide eventually leads to the Alzheimer's-related brain pathologies known as beta-amyloid plaques.


BACE1 does this by "cleaving," or breaking down, a protein called amyloid precursor protein. But BACE1 also cleaves other proteins, thus regulating important processes in the brain. Therefore, inhibiting it may cause some impairments as a side effect.


In fact, a range of studies referenced by the authors have shown that knocking out the BACE1 gene in mice leads to defects in the development of the neurons' axons, causing insufficient myelination — or the forming of the protective sheath around neurons — and even depression.


So, in the new study, the researchers wanted to reduce BACE1 more gently and gradually, in the hope that this would yield better results with fewer side effects. They genetically designed mice that would lose this enzyme bit by bit, as they aged.


The results of this laboratory experiment have now been published in the Journal of Experimental Medicine.




Alzheimer's could be 'completely reversed'


The mice went on to develop perfectly normally into adulthood. The scientists then proceeded to breed them with other rodents that had Alzheimer's-like symptoms, such as a buildup of amyloid plaque in the brain.


The subsequent offspring also started building up plaque in their brains from quite an early age. But as they got older and lost more and more of the BACE1 enzyme, their plaques started to gradually disappear.

In fact, by the time they were 10 months old, the mice had no detectable beta-amyloid plaques.


This was not the only sign of Alzheimer's that the enzyme loss helped to reverse: the mice's levels of beta-amyloid peptide also dropped, and microglia — brain cells that, when activated, had previously correlated with amyloid plaque density — were now deactivated.


Also, these neuronal changes were reflected in the mice's memory and learning abilities, which also improved.



"To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of Alzheimer's disease mouse models [...] Our study provides genetic evidence that pre-formed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult."


Riqiang Yan



He adds, "Our data show that BACE1 inhibitors have the potential to treat Alzheimer's disease patients without unwanted toxicity."


However, the study also found that the functioning of the synapses — that is, the spaces between neurons that facilitate their communication — was only partially restored. This suggested to the researchers that some BACE1 may be needed for synaptic health.


"Future studies," Yan says, "should develop strategies to minimize the synaptic impairments arising from significant inhibition of BACE1 to achieve maximal and optimal benefits for Alzheimer's patients."