Overexpression of Abeta is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in an amyotrophic lateral sclerosis mouse model.
Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate the motor impairment of human amyotrophic lateral sclerosis (ALS). The amyloid-beta (Abeta) peptide associated with Alzheimer's disease is neurotoxic. To investigate the potential role of Abeta in ALS development, we generated a double transgenic mouse line that overexpresses SOD1(G93A) and amyloid precursor protein (APP)-C100. The transgenic mouse C100.SOD1(G93A) overexpresses Abeta and shows earlier onset of motor impairment but has the same lifespan as the single transgenic SOD1(G93A) mouse. To determine the mechanism associated with this early-onset phenotype, we measured copper and zinc levels in brain and spinal cord and found both significantly elevated in the single and double transgenic mice compared with their littermate control mice. Increased glial fibrillary acidic protein and decreased APP levels in the spinal cord of C100.SOD1(G93A) mice compared with the SOD1(G93A) mice agree with the neuronal damage observed by immunohistochemical analysis. In the spinal cords of C100.SOD1(G93A) double transgenic mice, soluble Abeta was elevated in mice at end-stage disease compared with the pre-symptomatic stage. Buffer-insoluble SOD1 aggregates were significantly elevated in the pre-symptomatic mice of C100.SOD1(G93A) compared with the age-matched SOD1(G93A) mice, correlating with the earlier onset of motor impairment in the C100.SOD1(G93A) mice. This study supports abnormal SOD1 protein aggregation as the pathogenic mechanism in ALS, and implicates a potential role for Abeta in the development of ALS by exacerbating SOD1(G93A) aggregation.
Li
Qiao-Xin
QX
Department of Pathology, The University of Melbourne, and The Mental Health Research Institute of Victoria, Parkville, Vic. 3010, Australia. q.li@unimelb.edu.au
Mok
Su San
SS
Laughton
Katrina M
KM
McLean
Catriona A
CA
Volitakis
Irene
I
Cherny
Robert A
RA
Cheung
Nam Sang
NS
White
Anthony R
AR
Masters
Colin L
CL
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002470:Cell Survival; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009068:Movement / Q000502:physiology*; D018384:Oxidative Stress; D020836:Protein Structure, Quaternary; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; C000606290:SOD1 protein, human; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc