Inhibition of amyloid precursor protein beta-secretase cleavage site affects survival and motor functions of amyotrophic lateral sclerosis transgenic mice

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Recent studies have reported an increase in amyloid precursor protein (APP) levels and in its cleavage products in ALS patients indicating their possible involvement in this disease. APP is a transmembrane protein processed either by β-secretase or α-secretase followed by γ-secretase. The APP cleavage products - soluble APP-β (sAPPβ), amyloidogenic Aβ, and amino-terminal fragment N-APP - mediate a reduction in synaptic transmission, synaptic loss, neurite retraction and, ultimately, programmed cell death. Objective: To elucidate the role of APP cleavage products in the pathology of ALS. Methods: ALS mouse models that express mutant superoxide dismutase 1 were treated intraventricularly with a monoclonal antibody that blocks the β-secretase cleavage site on APP. Levels of the APP cleavage product called sAPPβ, motor functions and survival were assessed. Results: Inhibition of APP cleavage at a presymptomatic stage resulted in a decrease in the levels of sAPPβ, delay of disease onset and deterioration while at the symptomatic stage there was almost no beneficial effect. Conclusion: APP cleavage products might contribute to the degeneration in ALS, and early inhibition of the APP process may ameliorate disease progression.