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- Title
Overexpression of Aβ is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in an amyotrophic lateral sclerosis mouse model.
- Authors
Qiao-Xin Li; Su San Mok; Laughton, Katrina M.; McLean, Catriona A.; Volitakis, Irene; Cherny, Robert A.; Nam Sang Cheung; White, Anthony R.; Masters, Colin L.
- Abstract
Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate the motor impairment of human amyotrophic lateral sclerosis (ALS). The amyloid-β (Aβ) peptide associated with Alzheimer's disease is neurotoxic. To investigate the potential role of Aβ in ALS development, we generated a double transgenic mouse line that overexpresses SOD1G93A and amyloid precursor protein (APP)-C100. The transgenic mouse C100.SOD1G93A overexpresses Aβ and shows earlier onset of motor impairment but has the same lifespan as the single transgenic SOD1G93A 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.SOD1G93A mice compared with the SOD1G93A mice agree with the neuronal damage observed by immunohistochemical analysis. In the spinal cords of C100.SOD1G93A double transgenic mice, soluble Aβ 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.SOD1G93A compared with the age-matched SOD1G93A mice, correlating with the earlier onset of motor impairment in the C100.SOD1G93A mice. This study supports abnormal SOD1 protein aggregation as the pathogenic mechanism in ALS, and implicates a potential role for Aβ in the development of ALS by exacerbating SOD1G93A aggregation.
- Publication
Aging Cell, 2006, Vol 5, Issue 2, p153
- ISSN
1474-9718
- Publication type
Academic Journal
- DOI
10.1111/j.1474-9726.2006.00200.x