Employing a complex series of mouse models, a team of neurological disease researchers showed that reducing the level of the enzyme beta-secretase (BACE1) could reverse the clinical indication of Alzheimer’s disease (AD).An important element in the disease process in AD is the accretion of amyloid beta (Abeta) protein. To form Abeta, amyloid precursor protein (APP) must be cut by two enzymes, beta-secretase, and gamma-secretase. Drugs to block the beta-secretase enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and may help slow or stop Alzheimer’s disease. However, the consequence of studies on BACE inhibitors has raised the hazard that the drugs currently being investigated for the treatment of Alzheimer’s may have significant side effects associated with impaired motor coordination.
Since mice that completely lack BACE1 suffer severe neurodevelopmental defects, investigators at the Cleveland Clinic (OH, USA) scrutinize the possibility that inhibiting BACE1 in adult animals might be less harmful. To this end, they generated a strain of mice that gradually lost this enzyme as they grew older.
The investigators crossed these mice with a strain that started to develop amyloid plaques and Alzheimer’s disease when they were about 75 days old. The resulting offspring also formed plaques at this age, even though their BACE1 levels were approximately 50% lower than normal. However, the plaques began to disappear as the mice aged and lost BACE1 activity, until, at 10 months of age, the mice had no plaques in their brains at all.
This reversal in amyloid deposition caused significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques.
“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,” said senior author Dr. Riqiang Yan, now a professor of neuroscience at the University of Connecticut (Storrs, USA). “Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult. 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”.