Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
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.
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
J Barney
JB
Bryson
Carl
C
Hobbs
Michael J
MJ
Parsons
Karen D
KD
Bosch
Amelie
A
Pandraud
Frank S
FS
Walsh
Patrick
P
Doherty
Linda
L
Greensmith
D019943:Amino Acid Substitution / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001284:Atrophy; D001835:Body Weight; D002470:Cell Survival; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011499:Protein Processing, Post-Translational; D012995:Solubility; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1