A study carried out by experts from the Cleveland Clinic Lerner Research Institute in Ohio (USA) reveals that attacking an enzyme called BACE1 can “completely reverse” the accumulation 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 offer hope that one day humans may benefit from the same treatment.
The researchers, by Riqiang Yan of the Department of Neuroscience at the University of Connecticut School of Medicine, explain that the enzyme in question helps produce the beta amyloid peptide. An excessive accumulation of this peptide ultimately leads to Alzheimer’s-related brain pathologies known as beta-amyloid plaques.
The BACE1 enzyme does this by “cleaving” or breaking down a protein called amyloid precursor protein and also other proteins that regulate important processes in the brain. Inhibiting it with drugs is tricky because because BACE1 controls many important processes by cleaving proteins other than APP (amyloid precursor protein), these drugs could have serious side effects.
In fact, previous research has shown that knocking out of the BACE1 gene in mice leads to defects in the development of the axons of neurons, causing insufficient myelination and even depression.
Therefore, in the new study, the researchers intended to reduce this enzyme more gently and gradually, in the hope that it would produce better results with fewer side effects. Thus, they genetically engineered mice that would lose this enzyme little by little as they age.
Completely reversed disease
The mice developed perfectly normally in adulthood. They proceeded to breed them with other rodents that had Alzheimer’s-like symptoms, such as amyloid plaque buildup in the brain.
Later offspring of rodents also began to accumulate plaque in their brains from a fairly young age. But as they got older, and they lost more of the BACE1 enzyme, their plaques gradually began to fade. In fact, at 10 months, the mice had no detectable beta-amyloid plaques.
This was not the only sign that the enzyme loss helped reverse Alzheimer’s: the mice’s beta-amyloid peptide levels also decreased, and microglia, brain cells that, when activated, had previously correlated with density. amyloid plaque, they were now deactivated.
In addition, these neural changes were also reflected in the memory and learning abilities of the mice, which also improved.
“To our knowledge, this is the first observation of such a dramatic reversal of amyloid deposition in any study of mouse models of Alzheimer’s disease,” explains Riqiang Yan, leader of the work. “Our data show that BACE1 inhibitors have the potential to treat Alzheimer’s disease patients without unwanted toxicity,” he clarifies.
Reference: BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. Xiangyou Hu, Brati Das, Hailong Hou, Wanxia He, Riqiang Yan. Journal of Experimental Medicine 2018 DOI: 10.1084 / jem.20171831
