Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Transgenic mouse models show features that closely mimic those seen in the clinical situation, reflected in the molecular changes observed in mouse models and in tissues from patients. We report a dramatic increase in the expression of amyloid precursor protein (APP) in the hindlimb muscles, but not the spinal cord of the G93A transgenic mouse model, significantly before the appearance of clinical abnormalities. APP levels were unchanged in nontransgenic mice and in mice overexpressing human wild-type Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate a similar change in APP expression in human deltoid muscle samples from ALS patients compared with age-matched controls. The inhibitory role of APP in innervation at the neuromuscular junction and increased expression in inclusion-body myositis suggest that presymptomatic upregulation of APP may be consistent with a potential role for APP in ALS pathology.