β-amyloid 42 accumulation in the lumbar spinal cord motor neurons of amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of large motor neurons in the brain and spinal cord. Amyloid precursor protein (APP), the transmembrane precursor of beta-amyloid (A), accumulates in the anterior horn motor neurons of ALS patients with mild lesions. APP undergoes an alternative proteolysis mediated by caspase-3, which is activated in motor neurons in a mouse model of ALS. The ALS spinal cord motor neurons also show evidence of increased oxidative damage, which is thought to alter APP processing. We sought to determine whether A beta 42, the more pathogenic A species, accumulates in the postmortem lumbar spinal cord of ALS patients. While there was little or no A beta 42 labeling in control spinal cord tissues, elevated A beta 42 immunoreactivity occurred in ALS motor neuronal perikarya and axonal swellings in the anterior horn. A few A beta 42-positive neurons exhibited thioflavine S staining. No extracellular A beta 42 deposits were found. A beta 42 coexisted with the oxidative damage markers malondialdehyde, 8-hydroxydeoxyguanosine, heme oxygenase-1, and nitrotyrosine in abnormal neurons. The neurons with intracellular A 42 accumulation also displayed robust cleaved caspase-3 immunoreactivity. Very little A beta 40 immunoreactivity occurred in motor neurons of both control and ALS. These results suggest that aberrant accumulation of A beta 42 in ALS spinal cord motor neurons is associated with oxidative stress, and may play a role in the pathogenesis of neurodegeneration in ALS. (c) 2005 Elsevier Inc. All rights reserved.