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Beta-Amyloid, Oxidative Stress and Down Syndrome

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Down syndrome (DS) provides a model for studying important aspects of Alzheimer disease (AD). Chromosome 21 contains several genes that have been implicated in neurodegenerative mechanisms. These include Cu/Zn superoxide dismutase (SOD-1), Ets-2 transcription factors, Down Syndrome Critical Region 1 (DSCR1) stress-inducible factor, and the amyloid precursor protein (APP). The accumulation of Aβ plaques is progressive across the lifespan in DS. Overexpression of APP in the obligate region for DS is associated with abundant Aβ plaques and tangles consistent with Braak stage V-VI. Intraneuronal Aβ in DS appears to trigger a pathological cascade leading to oxidative stress and a neurodegeneration typical of AD. There are suggestions that an increase in subcellular processing of APP and factors related to membrane APP cleavage favor the secretion of Aβ with age in DS. A misbalance between SOD-1 and glutathione perioxidase activity in DS has been linked to free radical generation. Ets-2 and DSCR1 overexpression in DS has been linked to cell degeneration. Age-related accumulation of somatic DNA mutations in both DS and AD contribute to oxidative stress that exacerbates the imbalance in gene expression. This leads to enhanced Aβ deposition and further neuronal vulnerability. The consequence of these factors and their temporal relationships is likely to be the subject of future research. Since the pathological processes leading to AD are seen across the lifespan in DS, an opportunity is afforded for early pharmacological intervention in the disorder.

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Keywords: Alzheimer disease; ; DSRC1 stress-inducible factor; Down syndrome; Ets-2 transcription factor; SOD-1; amyloid; oxidative stress; somatic DNA mutations

Document Type: Research Article

Affiliations: Department of Pediatrics-ZC 4482, University of California, Irvine Medical Center, 101 The City Drive South, Orange, CA 92868, USA.

Publication date: December 1, 2006

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  • Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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