A recent study in mice showed that BACE inhibitors not only reduce cerebral amyloid-beta (Aβ) levels, but they also may improve the neural circuit and memory impairments in patients with Alzheimer’s disease. Researchers now plan to conduct a large-scale clinical trial with about 1,000 patients to determine in the unexpected and encouraging results found in mouse models can be replicated in humans.
The study titled, “BACE inhibition-dependent repair of Alzheimer’s pathophysiology,” was published in the journal Proceedings of the National Academy of Sciences of the United States of America.
“What really impressed and amazed us was the reversibility of the symptoms,” said Aylin Keskin, lead author of the publication. “Before the treatment, the mice had a marked clinical picture with amyloid beta plaques in their brain. Nevertheless, the substance was able to restore important brain functions and abilities.”
The presence of Aβ plaques is a major characteristic of the brains of Alzheimer’s disease patients. Aβ is produced through the work of a key enzyme called β-secretase BACE, and inhibitors for this particular enzyme are currently being used to treat Alzheimer’s disease in clinical trials.
The basic hypothesis behind the manifestation of Alzheimer’s disease is that the abnormal accumulation of Aβ plaques in the brain leads to neuronal dysfunction and eventually memory impairment. However, experiments conducted with other substances, such as antibodies against Aβ plaques, have shown variable results in terms of restoring neuronal function.
Therefore, researchers at Technical University of Munich set out to determine the relationship between Aβ plaques and the disease pathology of Alzheimer’s. Their study made use of a new compound that decreases Aβ plaques by inhibiting β-secretase BACE. Using mouse models of Alzheimer’s disease, the research team examined whether this compound was able to restore the neural circuit and memory impairment in these mice.
Neural circuits exhibit “hyperactivity” when stimulated by Aβ plaques, which eventually lead to the unfortunate consequences of Alzheimer’s disease. Results from this study also indicated that neuronal hyperactivity is actually a result of prefibrillary Aβ species, which are not a part of the core of the plaque but instead surround it.
Results from this study provided significant evidence that the presence of Aβ plaques in the brain leads to neural circuit dysfunction, which ultimately leads to cognitive and memory impairment. Researchers successfully demonstrated that the inhibition of the β-secretase BACE enzyme leads to a repair of the neural circuits that are damaged to the abnormal Aβ accumulation.
The study suggests that even the most dysfunctional neurons could have their activity recovered and that the “hyperactive” cells could be reversed to function normally. These events initiated by the BACE inhibitor leads to recovery of neural circuits, including memory function. Because previous studies have indicated that Alzheimer’s disease at an advanced state is mostly irreversible, the team was surprised by these reults and are encouraged as they move into planning a large-scale clinical trial to test a slightly modified form of the BACE inhibitor. “Needless to say, we very much hope that the promising discoveries in the animal model will translate to humans,” said Dr Marc Aurel Busche, young investigator group leader at the Institute for Neuroscience of the TUM and psychiatrist in the Department of Psychiatry and Psychotherapy of the TUM university hospital rechts der Isar.
