Neuronal cell death in Down's syndrome.
Down's syndrome (DS), occurring in 0.8 out of 1,000 live births, is a genetic disorder in which an extra portion of chromosome 21 leads to several abnormalities. With respect to the nervous system, it causes mental retardation. It is conceived that abnormal neuronal cell death in development is involved, but there is no direct evidence yet. In addition to developmental brain abnormalities, almost all DS brains over 40 years old manifest a similar pathology to Alzheimer's disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although there was a debate to segregate dementia from underlying mental retardation, at least some portion of DS patients exhibit deteriorated mental status with aging. The mechanism underlying these abnormalities at the molecular level remains to be elucidated. Recently there have been several reports suggesting abnormalities reflecting increased risk to apoptosis in DS brains. Increased expression of several apoptosis-related genes (p53, fas, ratio of bax to bcl-2, GAPDH) in DS brains has been reported. Cultured neurons from both patients and model animals are reportedly more vulnerable to apoptosis. Overproduction of reactive oxygen species and its causative roles for increased apoptosis in DS tissues are suggested. One possible hypothesis is an increased susceptibility to apoptosis due to p53 overactivation in DS brains. A beta 42, a critical peptide for AD pathology from amyloid precursor protein (APP), can be detected in DS brains. A beta 42 is deposited in SP from an early stage, suggesting common molecular mechanisms in DS and AD. Animal models for DS are important in the search of molecular mechanisms. Several types of models are now available. Future DS studies are expected to integrate information from animal models and human tissues.
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Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. akira@welchlink.welch.jhu.edu
D000328:Adult; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D002891:Chromosomes, Human, Pair 21; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D015994:Incidence; D009474:Neurons / Q000473:pathology*