Beta secretase inhibitors to treat Alzheimer's disease

April 2, 2015, Elsevier
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

With each new amyloid-targeting treatment for Alzheimer's disease that has been developed, there has been a corresponding concern. For example, antibodies targeting amyloid-β peptide (Aβ) produce inflammation in the brain in some patients. Gamma secretase inhibitors tend to produce adverse effects by interacting with Notch, an important pathway for cellular signaling.

Beta secretase 1 (BACE1) inhibitors are a new and promising target for Alzheimer's disease. Inhibiting BACE1 will limit the production of Aβ which, in turn, should reduce the production of neurotoxic fibrils and plaques.

"Since several BACE1 inhibitors are currently being evaluated in clinical phase 3 trials for the treatment of Alzheimer's disease, the identification of potential side effects will be of great importance to ensure a positive clinical outcome," said Dr. Jochen Herms, a Professor of translational brain research at Ludwig-Maximilians-University Munich.

He and his team have now gathered that data by exploring the impact of long-term BACE1 inhibition on dendritic spine dynamics, synaptic functions, and cognitive performance in adult mice. Their work is published in the current issue of Biological Psychiatry.

They found that pharmacological BACE1 inhibition reduced dendritic spine dynamics, reduced neurotransmission, and impaired cognition. Importantly, however, these disruptive effects were dose dependent.

Dr. Herms explained, "Our study demonstrates that moderate inhibition of BACE1 might be therapeutically efficient without any overt signs of health impairments. On the contrary, we found that strong inhibition of BACE1 in mice causes structural and functional synaptic alterations with deterioration of ."

Dr. John Krystal, Editor of Biological Psychiatry, commented, "Alzheimer's disease presents such a terrible burden on individuals, families, and society that if BACE1 inhibitors produce beneficial effects on the course of this disorder, it is well worth the effort to try to understand and circumvent this new risk."

Indeed, the clinical efficacy of BACE1 inhibitors remains unknown until the phase 3 trials currently underway are completed. In the meantime, these findings suggest that careful dosage of BACE1 will be necessary to avoid potential . The authors urge utmost caution in the dosage of drugs targeting BACE1 in order to achieve a therapeutic window that balances both safety and efficacy.

Explore further: Alzheimer's plaques reduced by targeting sugar attachment to the BACE1 enzyme

More information: The article is "Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions" by Severin Filser, Saak V. Ovsepian, Mercè Masana, Lidia Blazquez‐Llorca, Anders Brandt Elvang, Christiane Volbracht, Marianne B. Müller, Christian K.E. Jung, and Jochen Herms (DOI: 10.1016/j.biopsych.2014.10.013). The article appears in Biological Psychiatry, Volume 77, Issue 8 (April 15, 2015)

Related Stories

Alzheimer's plaques reduced by targeting sugar attachment to the BACE1 enzyme

January 15, 2015
Researchers at the RIKEN-Max Planck Joint Research Center in Japan have demonstrated that hallmark symptoms of Alzheimer's disease can be reduced when sugars are prevented from binding to one of the key enzymes implicated ...

Alzheimer's disease protein controls movement in mice

June 21, 2013
Researchers in Berlin and Munich, Germany and Oxford, United Kingdom, have revealed that a protein well known for its role in Alzheimer's disease controls spindle development in muscle and leads to impaired movement in mice ...

Enzyme BACE1 may be important in predicting onset of Alzheimer disease

December 12, 2013
The critical enzyme beta-secretase1 (BACE1) is known to be elevated in brains with sporadic Alzheimer disease (AD). Scientists have now found increased levels of BACE1 in brains with mild cognitive impairment (MCI), suggesting ...

Brain enzyme is double whammy for Alzheimer's disease

August 20, 2012
The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. β-amyloid is formed by the activity ...

Team finds regulator of amyloid plaque buildup in Alzheimer's disease

January 23, 2014
Scientists from the Florida campus of The Scripps Research Institute have identified a critical regulator of a molecule deeply involved in the progression of Alzheimer's disease.

Poor recycling of BACE1 enzyme could promote Alzheimer's disease

November 21, 2011
Sluggish recycling of a protein-slicing enzyme could promote Alzheimer's disease, according to a study published online on November 21 in The Journal of Cell Biology.

Recommended for you

Exercise may delay cognitive decline in people with rare Alzheimer's disease

September 25, 2018
For individuals carrying a genetic mutation that causes Alzheimer's disease, engaging in at least 2.5 hours of physical activity per week may have beneficial effects on markers of Alzheimer's disease brain changes and may ...

Scientists reveal ground-breaking plan to target cause of Alzheimer's disease

September 24, 2018
A breakthrough has been made in the fight against Alzheimer's disease—researchers have found a new way to target the toxic particles that destroy healthy brain cells.

A biomarker in the brain's circulation system may be Alzheimer's earliest warning

September 24, 2018
USC scientists say Alzheimer's could be diagnosed earlier if scientists focus on an early warning within the brain's circulation system.

In landmark study, doctors say test identifies people most likely to get Alzheimer's

September 24, 2018
The beginning was the worst. It frustrated Janet Parkerson when her father started to forget what he had done that day or the day before.

Study clarifies ApoE4's role in dementia

September 20, 2018
ApoE4, a protein linked to both Alzheimer's disease and a form of dementia caused by damage of blood vessels in the brain, increases the risk of cognitive impairment by reducing the number and responsiveness of blood vessels ...

Machine learning IDs markers to help predict Alzheimer's

September 19, 2018
Nearly 50 million people worldwide have Alzheimer's disease or another form of dementia. These irreversible brain disorders slowly cause memory loss and destroy thinking skills, eventually to such an extent that self-care ...

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.