Alzheimer’s drug helps initiate neuron repair

Researchers at the Hopkins School of Medicine have discovered a possible treatment for traumatic nerve injuries from an unexpected source: an experimental drug used for combating Alzheimer’s disease.

Their study, published in The Journal of Neuroscience earlier this month, investigates the effects of BACE1, a proteolytic enzyme, on neuron cells. BACE1 cleaves another protein that is necessary for the formation of myelin, a fatty substance that surrounds the elongated areas of neurons. Myelin increases the speed and rate that electrical signals are transmitted by neurons.

High levels of BACE1 are seen in the brains of Alzheimer’s patients. The protein is thought to be involved in the buildup of the protein plaques in these patients’ brains. These plaques are directly responsible for the decrease in electrical signals and thus, are responsible for the symptoms of Alzheimer’s disease.

Because of this, scientists believe BACE1 inhibition could serve as a viable method for treating Alzheimer’s. However, what the team was most interested in was seeing how BACE1 activity affects the regenerative capability of damaged neurons. Most damage to neurons falls under two broad categories: peripheral neuropathy, which is any physical damage to neurons that are not located in the brain or spinal cord, and spinal cord injuries.

Using mice as a model system, the researchers examined two groups. The first, those that expressed the gene that codes for BACE1 at normal levels, acted as the control. The second were knockout mice: the gene for BACE1 had been completely removed from their DNA, rendering the mice incapable of synthesizing the protein.

Neuronal damage was induced by two methods: by using paclitaxel, a cancer treatment drug that also causes neuronal degeneration, or by using acrylamide, a neurotoxin. Their first observation was that there was no significant change in the initial range of degeneration of axons. The effects of exposure to paclitaxel and acrylamide were independent of whether or not the individual mouse expressed BACE1.

In contrast, there was a marked difference in the subsequent regeneration of the damaged neurons. Knockout mice exhibited an accelerated rate of clearance of the axonal and myelin debris that resulted from the degeneration caused by the toxins.

In knockout mice, debris was almost completely cleared 10 days after treatment in comparison to 15 days in wild-type mice.

They visualized this clearance by introducing a gene for yellow fluorescent protein (YFP) into the mice’s DNA. YFP is a derivative of green flouorescent protein (GFP), a green counterpart that naturally occurs in the species of jellyfish, Aequorea victoria. Under a microscope, the debris fluoresced yellow, and the amount of debris was measured at different times. According to the authors, previous studies have determined that the presence of debris negatively affects the ability of damaged neurons to regenerate.

This was supported by their final observation that BACE1 knockout mice exhibited faster re-growth of their elongated parts: there was a higher number of new “axonal sprouts” (the beginnings of new neurons) than compared to neurons of wild-type mice.

The implications of this discovery go far beyond the original purpose of investigating BACE1’s role in Alzheimer’s. As Mohamed Farah said in a press release, “Anything that speeds nerve regrowth could be enormously helpful to people with nerve injuries caused by a range of injuries and diseases from diabetic neuropathy to motorcycle accidents.”