Down Syndrome Research Today is a free monthly online journal that collates and summarizes the latest research about Down Syndrome, including details on education, symptoms, treatment, information.

Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition.

Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA

Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.

An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of betaCTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced Abeta production but raised betaCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the betaCTF of APP, and exclude Abeta and the alphaCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.

Published 5 February 2010 in Proc Natl Acad Sci U S A, 107(4): 1630-5.
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Articles on Down Syndrome published 5 February 2010:

Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group.   Blood, 115(5): 1006-17.

We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions ... [Abstract] [Full-text]

Articles on Down Syndrome published 11 January 2010:

Neutrophil oxidative metabolism in Down syndrome patients with congenital heart defects.   Environ Mol Mutagen, 51(1): 57-63.

Down syndrome (DS) occurs when an individual has three, rather than two, copies of the 21st chromosome. Cytosolic superoxide dismutase (SOD-1) is encoded by a gene on chromosome 21 and thus, SOD-1 activity is elevated in patients with DS. Forty percent of all cases with DS are associated with congenital heart defects (CHD). Although the contribution of SOD1 to disease phenotype is unknown, it is considered to be a "molecular marker" of the disease. It was hypothesized herein that the ... [Abstract] [Full-text]

Articles on Down Syndrome published 6 January 2010:

Spinal myxopapillary ependymoma with Down syndrome: exploring an unusual association.   J Pediatr Hematol Oncol, 32(1): e38-41.

SUMMARY: In patients with Down syndrome, cancers like leukemia and testicular tumors are frequent, but association with central nervous system tumors is rare. Only 1 case of ependymoma has been observed as an incidental autopsy finding in a 19-week-old female fetus. We herein report the second case of ependymoma and the fifth case of spinal tumor occurring in association with Down syndrome. We have also attempted to elucidate the various mechanisms of tumorigenesis implicated in this multiple ... [Abstract] [Full-text]

Articles on Down Syndrome published 4 January 2010:

Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains.   J Biol Chem, 285(2): 1529-43.

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA ... [Abstract] [Full-text]

Articles on Down Syndrome published 30 December 2009:

Synergy of total PLAC4 RNA concentration and measurement of the RNA single-nucleotide polymorphism allelic ratio for the noninvasive prenatal detection of trisomy 21.   Clin Chem, 56(1): 73-81.

BACKGROUND: Maternal plasma mRNA encoded by the PLAC4 gene (placenta-specific 4), which is transcribed from chromosome 21 in placental cells, is a potential marker for the noninvasive assessment of chromosome 21 dosage in the fetus. We evaluated the diagnostic sensitivities and specificities of 2 trisomy 21-screening approaches that use maternal plasma PLAC4 mRNA. METHODS: We studied maternal plasma samples from 153 pregnant women carrying euploid and trisomy 21 fetuses. For the samples in ... [Abstract] [Full-text]

Noninvasive prenatal detection of trisomy 21 by an epigenetic-genetic chromosome-dosage approach.   Clin Chem, 56(1): 90-8.

BACKGROUND: The use of fetal DNA in maternal plasma for noninvasive prenatal diagnosis of trisomy 21 (T21) is an actively researched area. We propose a novel method of T21 detection that combines fetal-specific epigenetic and genetic markers. METHODS: We used combined bisulfite restriction analysis to search for fetal DNA markers on chromosome 21 that were differentially methylated in the placenta and maternal blood cells and confirmed any target locus with bisulfite sequencing. We then used ... [Abstract] [Full-text]

Articles on Down Syndrome published 16 December 2009:

Mannan-binding lectin deficiency increases the risk of recurrent infections in children with Down's syndrome.   Hum Immunol, 71(1): 63-6.

Down syndrome (DS) is the most frequent cause of intellectual disability worldwide. DS individuals present abnormalities in the immune system that include high susceptibility to recurrent infections (RI) as well as to autoimmune diseases. Respiratory tract infections remain one of the major causes of death in DS individuals. Mannan-binding lectin (MBL) functions as an opsonina and initiates the lectin complement pathway. MBL deficiency was shown to increase the susceptibility to different ... [Abstract] [Full-text]

Articles on Down Syndrome published 1 December 2009:

Prevalence of Down syndrome among children and adolescents in 10 regions of the United States.   Pediatrics, 124(6): 1565-71.

OBJECTIVE: We aimed to estimate the prevalence of Down syndrome (DS) among children and adolescents aged 0 to 19 years in 10 regions of the United States. METHODS: This study was a cross-sectional analysis of live-born infants with DS during 1979-2003 from 10 population-based birth defects registries in the United States. We estimated the prevalence of DS at birth and among children aged 0 to 19 years in each region and in all regions pooled. The prevalence of DS among children and adolescents ... [Abstract] [Full-text]

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