BACE-Inhibitor successfully tested in Alzheimer's animal model

July 28, 2017, Technical University Munich
Marc Aurel Busche at the two-photon microscope, which allows to visualize nerve cells with high temporal and spatial resolution in the intact brain. Credit: Kurt Bauer / Technical University of Munich

The protein amyloid beta is believed to be the major cause of Alzheimer's disease. Substances that reduce the production of amyloid beta, such as BACE inhibitors, are therefore promising candidates for new drug treatments. A team at the Technical University of Munich (TUM) has recently demonstrated that one such BACE inhibitor reduces the amount of amyloid beta in the brain. By doing so, it can restore the normal function of nerve cells and significantly improve memory performance.

Around 50 million people worldwide suffer from dementia. To date, no effective drug is available that is able to halt or cure the disease. Moreover, the exact causes of the disease have yet to be definitively explained. However, there is a greater accumulation of the protein in Alzheimer's patients than in healthy people. As a result, the protein clumps together and damages nerve .

Affected cells can become hyperactive. They then constantly send false signals to neighboring cells. In addition, certain waves such as slow oscillations spin out of control. These waves play a key role in the formation of memories by transferring learned information into long-term memory.

Brain functions restored in mice

"A successful treatment must take effect as early in the course of the disease as possible. In our experiments, we have therefore blocked the enzyme beta secretase BACE, which produces amyloid beta," explains 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.

The researchers tested a substance that inhibits beta secretase in a mouse model of Alzheimer's. The produce large amounts of amyloid beta, which, as in humans, leads to the formation of in the brain and causes memory loss. During the study, the mice were given the inhibitor in their food for up to eight weeks, after which they were examined. For this purpose, the researchers used a special imaging technique known as two-photon microscopy, which allowed them to observe individual nerve cells in the brain.

As expected, the mice had less amyloid beta in their brain after this period, since its production was inhibited. However, the effect of the substance was much more far-reaching: the animals' brain functions actually normalized. There were fewer hyperactive nerve cells, and the slow-wave brain patterns once again resembled those in healthy mice. A key finding for the scientists was the observation that the animals' memory also improved. The mice were able to locate a hidden platform in a water-filled maze as quickly as their healthy counterparts.

Clinical trial planned

"What really impressed and amazed us was the reversibility of the symptoms. 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," explains Aylin Keskin, lead author of the publication. Moreover, the researchers' study showed yet another benefit: "We were also able to demonstrate which neural deficits really are caused by beta. That was not fully understood with regard to hyperactive , for example," Keskin says.

The scientists' findings will soon find its way into clinical practice: A large-scale clinical trial is planned with around 1000 participants 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", Busche says.

Explore further: 'Pac-Man' gene implicated in Alzheimer's disease

More information: A. D. Keskin, M. Kekuš, H. Adelsberger, U. Neumann, D. R. Shimshek, B. Song, B. Zott, T. Peng, H. Förstl, M. Staufenbiel, I. Nelken, B. Sakmann, A. Konnerth, and M. A. Busche, BACE inhibition-dependent repair of Alzheimer's pathophysiology, Proceedings of the National Academy of Sciences, July 2017 . DOI: 10.1073/pnas.1708106114 , http://www.pnas.org/content/early/2017/07/19/1708106114.abstract

Related Stories

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Genetically engineered mice suggest new model for how Alzheimer's causes dementia

July 4, 2016
Using a novel, newly developed mouse model that mimics the development of Alzheimer's disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological "insults" must ...

Key cellular auto-cleaning mechanism mediates the formation of plaques in Alzheimer's brain

October 3, 2013
Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer's disease. It might be a potential drug target for the treatment of the disease, concludes ...

Blocking inflammation prevents cell death, improves memory in Alzheimer's disease

February 29, 2016
Using a drug compound created to treat cancer, University of California, Irvine neurobiologists have disarmed the brain's response to the distinctive beta-amyloid plaques that are the hallmark of Alzheimer's disease.

Road block as a new strategy for the treatment of Alzheimer's

August 22, 2011
Blocking a transport pathway through the brain cells offers new prospects to prevent the development of Alzheimer's. Wim Annaert and colleagues of VIB and K.U. Leuven discovered that two main agents involved in the inception ...

Protein in the brain could be a key target in controlling Alzheimer's

January 25, 2012
A protein recently discovered in the brain could play a key role in regulating the creation of amyloid beta, the major component of plaques implicated in the development of Alzheimer's disease, according to researchers at ...

Recommended for you

New study suggests viral connection to Alzheimer's disease

June 21, 2018
Of the major illnesses facing humanity, Alzheimer's disease (AD) remains among the most pitiless and confounding. Over a century after its discovery, no effective prevention or treatment exists for this progressive deterioration ...

New screening tool could help diagnose early cognitive decline in dementia from home

June 19, 2018
An international team of scientists have developed a new way to screen for age-related cognitive decline at home using a test which asks people to detect sounds and flashes on their laptop or phone.

Genes linked to Alzheimer's contribute to damage in different ways

June 12, 2018
Multiple genes are implicated in Alzheimer's disease. Some are linked to early-onset Alzheimer's, a condition that develops in one's 30s, 40s and 50s, while others are associated with the more common late-onset form of the ...

Researchers reverse cognitive impairments in mice with dementia

June 8, 2018
Reversing memory deficits and impairments in spatial learning is a major goal in the field of dementia research. A lack of knowledge about cellular pathways critical to the development of dementia, however, has stood in the ...

As mystery deepens over the cause of Alzheimer's, researchers seek new answers

June 6, 2018
For more than 20 years, much of the leading research on Alzheimer's disease has been guided by the "amyloid hypothesis."

Research reveals how Tau aggregates can contribute to cell death in Alzheimer's disease

June 5, 2018
New evidence suggests a mechanism by which progressive accumulation of Tau protein in brain cells may lead to Alzheimer's disease. Scientists studied more than 600 human brains and fruit fly models of Alzheimer's disease ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.