Clinical signs of Alzheimer’s have been completely reversed by scientists targeting a specific brain protein, raising hopes of an effective treatment for the disease.
The US team bred Alzheimer’s-prone laboratory mice whose levels of the protein, an enzyme called BACE1, reduced as they got older.
Gradually depleting BACE1 cleared their brains of a toxic protein building block, beta-amyloid, that is a key hallmark of Alzheimer’s.
Other markers of the disease were also reversed, including the activation of microglial immune cells. Meanwhile, the animals’ learning and memory improved.
Lead scientist Dr Riqiang Yan, from the Cleveland Clinic, Ohio, said: “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.
“Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult.”
BACE1 plays a vital role in the formation of beta-amyloid brain plaques.
It has therefore been a prime target in attempts to develop Alzheimer’s treatments that do more than simply limit symptoms of the disease.
However, because the enzyme controls so many processes, suppressing it runs the risk of serious unwanted side effects.
The Cleveland team found evidence that some BACE1 may be required for optimal neural connectivity and mental performance.
“Future studies should develop strategies to minimise the synaptic impairments arising from significant inhibition of BACE1 to achieve maximal and optimal benefits for Alzheimer’s patients,” said Dr Yan.
The scientist began by creating mice genetically programmed to lose BACE1 slowly as they age.
These mice developed normally and appeared to remain perfectly healthy over time.
They were then bred with mice that start to develop beta-amyloid plaques and Alzheimer’s disease at 75 days old.
The resulting offspring inherited both traits – a vulnerability to Alzheimer’s and gradually declining BACE1 levels.
Despite having half as much of the enzyme as normal, they still developed toxic clumps of beta-amyloid in their brains after 75 days.
From then on, however, the plaques began to disappear as BACE1 activity reduced, until at 10 months old no trace of them remained at all.
Dr Sara Imarisio, from the charity Alzheimer’s Research UK, said: “Developing drugs that tackle Alzheimer’s disease by targeting the BACE1 protein is an active area of research.
“This new study adds to findings that suggest this approach is a promising avenue for future therapies, but drugs that target this protein are yet to show any benefit to people with Alzheimer’s in clinical trials.”