BACE1 Deletion Eliminates Amyloid Deposits in a Mouse Model of Alzheimer's Disease

BACE1 is one of the proteins involved in early stages of the production of amyloid-β, a form of metabolic waste that aggregates into solid deposits in the aging brain, and is characteristic of Alzheimer's disease. Inhibition of BACE1 so as to reduce levels of amyloid-β is a strategy pursued by a number of research groups, though it has to be said that disenchantment with the years of failure in the dominant strategy of clearing amyloid-β appears to be reaching a tipping point these days. While it is clear that amyloid-β is harmful, it may not be the most effective point of intervention. Or perhaps earlier efforts to remove amyloid-β were not going about it in the right way, and different approaches would work. It is very hard to say, as the aging brain is a complex mix of many different, interacting forms of damage and dysfunction.

The research here can be read as strong support for the BACE1 inhibition approach to Alzheimer's disease, given the size of the effect, though the same questions remain as in any other success in reducing amyloid from the mouse models of Alzheimer's disease. If none of the others successfully translated to human therapies, and failed in trials, how confident or hopeful should we be here? A great many people are asking themselves exactly that these days, which is why we can observe the growth of support for the impaired cerebrospinal fluid drainage model of Alzheimer's disease, or the microbial model of the condition, and a range of further theorizing on different causes and different priorities in research and development.

With a large swath of the population entering its senior years, the number of Alzheimer's disease (AD) cases are expected to skyrocket, placing a tremendous burden on the healthcare system. Yet, a glimmer of hope may have just emerged as investigators report that gradually depleting an enzyme called BACE1 completely reverses the formation of amyloid plaques in the brains of mice with AD, subsequently improving the animals' cognitive function. "To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of AD mouse models."

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 (BACE1fl/fl) mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model 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."

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.

Link: https://www.genengnews.com/gen-news-highlights/alzheimers-disease-reversed-in-mouse-model/81255493