Open AccessOverexpression of Aβ is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in an amyotrophic lateral sclerosis mouse model
Author(s) -
Li QiaoXin,
Mok Su San,
Laughton Katrina M.,
McLean Catriona A.,
Volitakis Irene,
Cherny Robert A.,
Cheung Nam Sang,
White Anthony R.,
Masters Colin L.
Publication year - 2006
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2006.00200.x
Subject(s) - sod1 , amyotrophic lateral sclerosis , genetically modified mouse , superoxide dismutase , biology , transgene , spinal cord , immunology , medicine , endocrinology , microbiology and biotechnology , oxidative stress , neuroscience , biochemistry , disease , gene
Summary 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 SOD1 G93A and amyloid precursor protein (APP)‐C100. The transgenic mouse C100.SOD1 G93A overexpresses Aβ 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 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.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 Aβ in the development of ALS by exacerbating SOD1 G93A aggregation.