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Beta secretase inhibitors offer treatment for Alzheimer’s disease


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. However, a new target for alzheimer’s is offering some new hope.

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.

The team has 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.

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

“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 cognitive performance,” Dr. Herms explained.

“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,” Dr. John Krystal, Editor of Biological Psychiatry, commented.

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 inhibitors will be necessary to avoid potential adverse effects. 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.

Filser, S., Ovsepian, S., Masana, M., Blazquez‐Llorca, L., Brandt Elvang, A., Volbracht, C., Müller, M., Jung, C., & Herms, J. (2015). Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions Biological Psychiatry, 77 (8), 729-739 DOI: 10.1016/j.biopsych.2014.10.013

One response

  1. Alzheimer’s Disease is indeed a very complex disease that effects many people in our world. It will be a glorious day when they finally find the cure to this disease. Based on my research, there has been many medications and inhibitors that have been put on trial to see if they will finally be the cure or at least the medication that will help people with this awful disease. The problem with all the drugs that I looked up is they all seemed to have side effects that were far greater than the benefits that the drug brings the person. This BACE1 inhibitor seems to be the same way. It does seem to help reduce plaque and fibrils in the brain that are the main biological side effects, but there is a list of negative side effects that are associated with it. These side effects are ones that will in all actually make this disease harder on the patient and the patients family. It reduces neurotransmission and cognitive functioning. This is one of the main signs of Alzheimer’s anyways, so way would someone want to take this medication and make their life more miserable. One of the hardest part of this disease on the patient is that they cannot remember people and how to do stuff. This medicine is said to make that worse. Why would we do this to someone? There must be a better medication or treatment option for someone with this disease. A treatment that will not decrease their already poor cognitive functioning and neurotransmission. I understand that decreasing the plaque will help to slow down the progress of the disease and maybe completely halt its progress, but most people would probably rather let the disease run its course than to live with poor cognitive functioning for a longer period of time. Do we want people to just be alive, or do we want them to actually have a good quality of life?


    May 3, 2015 at 6:04 pm

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