Beta-amyloid, oxidative stress and down syndrome.
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 Abeta plaques is progressive across the lifespan in DS. Overexpression of APP in the obligate region for DS is associated with abundant Abeta plaques and tangles consistent with Braak stage V-VI. Intraneuronal Abeta 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 Abeta 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 Abeta 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.
Lott
Ira T
IT
Department of Pediatrics and Neurology, Alzheimer Disease Research Center, University of California, Irvine, School of Medicine, Irvine, California 92868, USA. itlott@uci.edu
Head
Elizabeth
E
Doran
Eric
E
Busciglio
Jorge
J
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004314:Down Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D020271:Heredodegenerative Disorders, Nervous System / Q000209:etiology; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1