Beta-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 beta), 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 beta42, the more pathogenic A beta species, accumulates in the postmortem lumbar spinal cord of ALS patients. While there was little or no A beta42 labeling in control spinal cord tissues, elevated A beta42 immunoreactivity occurred in ALS motor neuronal perikarya and axonal swellings in the anterior horn. A few A beta42-positive neurons exhibited thioflavine S staining. No extracellular A beta42 deposits were found. A beta42 coexisted with the oxidative damage markers malondialdehyde, 8-hydroxydeoxyguanosine, heme oxygenase-1, and nitrotyrosine in abnormal neurons. The neurons with intracellular A beta42 accumulation also displayed robust cleaved caspase-3 immunoreactivity. Very little A beta40 immunoreactivity occurred in motor neurons of both control and ALS. These results suggest that aberrant accumulation of A beta42 in ALS spinal cord motor neurons is associated with oxidative stress, and may play a role in the pathogenesis of neurodegeneration in ALS.
Calingasan
Noel Y
NY
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, F-610, New York, NY 10021, USA. nyc2001@med.cornell.edu
Chen
Junyu
J
Kiaei
Mahmoud
M
Beal
M Flint
MF
D000328:Adult; D000368:Aged; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008161:Lumbosacral Region; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism*; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)