Molecular abnormalities of the brain in Down Syndrome: relevance to Alzheimer's neurodegeneration

Down syndrome is caused by over-expression of genes located within a segmen t of chromosome 21, termed the Down locus. Down syndrome is associated with developmental abnormalities of the central nervous system that result in m ental retardation and age-dependent Alzheimer-type neurodegeneration. Some of the neurodegenerative lesions, including A beta amyloid deposition, apop totic cell death, and aberrant dendritic arborization, are in part due to c onstitutively increased expression of genes that encode the amyloid precurs or protein, superoxide dismutase I, and S100-beta, and located within the D own locus. However, neurodegeneration in Down syndrome is also associated w ith aberrant expression of genes that are not linked to the Down locus, inc luding the growth associated protein, GAP-43, nitric oxide synthase 3, neur onal thread protein, and pro-apoptosis genes such as p53, Bar, and interleu kin-1 beta-converting enzyme. Increased expression of these non-Down locus genes correlates with proliferation of dystrophic neurites and apoptotic ce ll death, two important correlates of cognitive impairment in Alzheimer's d isease. This article reviews the functional importance of abnormal gene exp ression in relation to Alzheimer-type neurodegeneration in brains of indivi duals with Down syndrome.