Enhanced β-secretase processing of amyloid precursor protein in the skeletal muscle of ALS animal models

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder primarily characterized by motor neuron degeneration and muscle paralysis. Several studies indicate that pathological changes in the skeletal muscle contribute to disease progression. We report a significant increase of β-secretase processing of amyloid precursor protein (APP) in the skeletal muscle but not the spinal cord or cerebral cortex of hSOD1 (G93A) transgenic ALS mouse models. Enhanced β-secretase processing of APP was manifested by up-regulated expression of βCTF, the 22-kd CTF of APP, and β-secretase processing enzyme, BACE1. Morphological analysis demonstrated that enhanced β-secretase processing of APP mainly occurred in the atrophic myofibers of ALS mice. We also observed a similar change in APP processing in an hSOD1 (G93A) transgenic ALS pig model, suggesting that enhanced β-secretase processing of APP in skeletal muscle may be a common pathological feature of ALS. These findings reveal a selective change in APP processing in skeletal muscle of ALS animal models, and highlight the involvement of aberrant APP processing in ALS pathogenesis.