Researchers
Successfully Reverse
Alzheimer’s Disease in Mouse Model
Newswise
from Rockefeller University Press, February 7, 2018 — A team of researchers
from the Cleveland Clinic Lerner Research Institute have found that gradually
depleting an enzyme called BACE1 completely reverses the formation of amyloid
plaques in the brains of mice with Alzheimer’s disease, thereby improving the
animals’ cognitive function. The study, which will be published February 14 in
the Journal of Experimental Medicine,
raises hopes that drugs targeting this enzyme will be able to successfully
treat Alzheimer’s disease in humans.
One
of the earliest events in Alzheimer’s disease is an abnormal buildup of
beta-amyloid peptide, which can form large, amyloid plaques in the brain and
disrupt the function of neuronal synapses. Also known as beta-secretase, BACE1
helps produce beta-amyloid peptide by cleaving amyloid precursor protein (APP).
Drugs that inhibit BACE1 are therefore being developed as potential Alzheimer’s
disease treatments but, because BACE1 controls many important processes by
cleaving proteins other than APP, these drugs could have serious side effects.
Mice
completely lacking BACE1 suffer severe neurodevelopmental defects. To investigate
whether inhibiting BACE1 in adults might be less harmful, Riqiang Yan and
colleagues generated mice that gradually lose this enzyme as they grow older.
These mice developed normally and appeared to remain perfectly healthy over
time.
The
researchers then bred these rodents with mice that start to develop amyloid
plaques and Alzheimer’s disease when they are 75 days old. The resulting
offspring also formed plaques at this age, even though their BACE1 levels were
approximately 50% lower than normal. Remarkably, however, the plaques began to
disappear as the mice continued to age and lose BACE1 activity, until, at 10
months old, the mice had no plaques in their brains at all.
“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,” says Yan,
who will be moving to become chair of the department of neuroscience at the University of Connecticut
Decreasing
BACE1 activity also resulted in lower beta-amyloid peptide levels and reversed
other hallmarks of Alzheimer’s disease, such as the activation of microglial
cells and the formation of abnormal neuronal processes.
Loss
of BACE1 also improved the learning and memory of mice with Alzheimer’s
disease. However, when the researchers made electrophysiological recordings of
neurons from these animals, they found that depletion of BACE1 only partially
restored synaptic function, suggesting that BACE1 may be required for optimal
synaptic activity and cognition.
“Our
study provides genetic evidence that preformed amyloid deposition can be
completely reversed after sequential and increased deletion of BACE1 in the
adult,” says Yan. “Our data show that BACE1 inhibitors have the potential to
treat Alzheimer’s disease patients without unwanted toxicity. Future studies
should develop strategies to minimize the synaptic impairments arising from
significant inhibition of BACE1 to achieve maximal and optimal benefits for
Alzheimer’s patients.”
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