Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS), the progressive loss of motor neurons is accompanied by extensive muscle denervation, resulting in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS patients and the SOD1. G93A mouse model of familial ALS. We have further characterized this response in SOD1. G93A mice and also revealed elevated levels of β-amyloid (Aβ) peptides in the SOD1. G93A spinal cord, which were predominantly localized within motor neurons and their surrounding glial cells. We therefore examined the effect of genetic ablation of APP on disease progression in SOD1. G93A mice, which significantly improved multiple disease parameters, including innervation, motor function, muscle contractile characteristics, motor unit and motor neuron survival. These results therefore strongly suggest that APP actively contributes to SOD1. G93A-mediated pathology. Together with observations from ALS cases, this study indicates that APP may contribute to human ALS pathology. © The Author 2012. Published by Oxford University Press. All rights reserved.