Alzheimer's Disease Reversed in Mouse Model

With a large swath of the population entering its senior years, the number of Alzheimer’s disease (AD) cases is expected to skyrocket, placing a tremendous burden on the healthcare system. Yet, a glimmer of hope may have just emerged as investigators from the Cleveland Clinic Lerner Research Institute (CCLRI) have found that gradually depleting an enzyme called BACE1 completely reverses the formation of amyloid plaques in the brains of mice with AD, thereby improving the animals’ cognitive function.

Findings from the new study – published in The Journal of Experimental Medicine in an article entitled “BACE1 Deletion in the Adult Mouse Reverses Preformed Amyloid Deposition and Improves Cognitive Functions” – raises hopes that drugs targeting this enzyme will be able to treat AD in humans successfully.

“To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of AD mouse models,” remarked senior study investigator Riqiang Yan, Ph.D., professor of molecular medicine and vice chair in biomedical research at CCLRI.

One of the earliest events in AD is an abnormal buildup of the beta-amyloid (Aß) 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 the Aß peptide by cleaving the amyloid precursor protein (APP). Drugs that inhibit BACE1 are therefore being developed as potential AD 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, the research team generated mice that gradually lose this enzyme as they grow older. These mice developed normally and appeared to remain perfectly healthy over time.

“To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1^fl/fl) mice and bred BACE1^fl/fl mice with ubiquitin-Cre^ER mice to induce deletion of BACE1 after passing early developmental stages,” the authors wrote. “Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in 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.”

The CCLRI team bred these rodents with mice that start to develop amyloid plaques and AD 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 ten months old, the mice had no plaques in their brains at all.

Additionally, decreasing BACE1 activity also resulted in lower Aß peptide levels and reversed other hallmarks of AD, such as the activation of microglial cells and the formation of abnormal neuronal processes.

Remarkably, the loss of BACE1 also improved the learning and memory of mice with AD. 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,” concluded Dr. Yan. “Our data show that BACE1 inhibitors have the potential to treat AD 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.”