Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by β-secretase or α-secretase, followed by γ-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced β-secretase cleavage, are increased in SOD1G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP β-secretase cleavage site, resulted in reduction of mutant SOD1G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPβ and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by degeneration of both upper and lower motor neurons, leading to muscle denervation and atrophy[1]
The effect of mutant superoxide dismutase 1 (SOD1) on Amyloid precursor protein (APP) expression was evaluated throughout the disease progression in SOD1G93A ALS mouse model
Since astrocytes play a major role in ALS pathology [25], and it was previously shown that BBS leads to reduction in the levels of activated astrocytes marker glial fibrillary acidic protein (GFAP), we examined the effect of BBS treatment on astrogliosis in SOD1G93A mice
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by degeneration of both upper and lower motor neurons, leading to muscle denervation and atrophy[1]. Sporadic ALS accounts for close to 90% of all ALS cases and the remaining 10% are considered familial cases, about 20% of which are caused by a dominant mutation in the gene encoding superoxide dismutase 1 (SOD1)[2]. Mutant SOD1 murine models mimic many of the clinical. APP and Mutant SOD1 in ALS the authors hold any equity in NasVax Ltd, Israel. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors
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