Functional Improvement by Enhancing Plasticity and Reinnervation in ALS Mouse Model
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating and debilitating neurodegenerative disease without a cure or effective treatment. Over the years, insightful clues to cellular dysfunctions at the earlier stages of ALS have been elucidated. A key pathological damage resulting in functional impairment happens early in the disease course: The neural input to muscle diminishes as motor axons connecting to muscle degenerate, leading to muscle wasting. At the same time, surviving axons attempt to compensate for the loss by a process known as collateral sprouting, but this eventually fails. A plausible intervention at the early stages of disease would be to enhance and strengthen these regenerative and adaptive compensatory attempts. Such interventions might improve the quality of life and slow down the disease course, and are much needed therapies. The strategies aimed at promoting motor axon regrowth from surviving axons might lead functional restoration by reinnervation of muscles. We previously discovered that genetic engineering of mice enhances peripheral nerve regeneration following sciatic nerve crush injury in mice. We have discovered that when an enzyme (BACE1) is inactivated, motor axons regrow much faster compared to control conditions. This prompted us to explore the possibility that pharmacological inhibition of BACE1 might be an effective means to encourage collateral sprouting of intact motor axons at an early stage of ALS. This possibility is attractive given that the pharmaceutical industry is actively developing BACE1 inhibitors as candidate therapies for Alzheimer s disease and is therefore amassing safety, efficacy, and biodistribution data on these molecules. Therefore, if this proposal generates useful data, then a path to testing BACE1 inhibitor in ALS will emerge faster. Here, we present preliminary data to suggest that a small-molecule BACE1 inhibitor improves motor axon sprouting and restores nerve function in a mouse model of ALS, the SOD1 mouse. In this proposal, we will explore BACE1 inhibitors (at different doses) as potential therapies for early stages of ALS mouse model and at multiple time points of the disease progression. We also plan to investigate the mechanism of action of BACE1 inhibitors at the molecular level in the context of motor axon sprouting. If our proposal shows beneficial results in preclinical studies on mice, BACE1 inhibitors can be rapidly tested in ALS, particularly at early stages and for slowly progressing forms of the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910229
Entities
People
- Mohamed H. Farah
Organizations
- Johns Hopkins University
- United States Army