Syndrome Brain Research Articles

Manifold Reduction of Moesin in Fetal Down Syndrome Brain

Moesin is a member of the ERM family and is involved in plasma membrane–actin cytoskeleton cross-linking, resulting cell adhesion, shape, and motility. Because moesin was shown to be highly expressed in growth cones and moesin/radixin suppression led to impaired structure and function of this key element in brain development, we tested the ERM family, ezrin, radixin, and moesin, in fetal Down syndrome (DS) cortex at the early second trimester. We applied two-dimensional gel electrophoresis with subsequent MALDI detection and identification of protein spots followed by quantification with specific software. Moesin was shown to be significantly and manifold reduced in fetal DS brain, whereas reduction of ezrin and radixin did not reach statistical significance. We therefore propose the involvement of moesin in developmental impairment of DS brain, including deteriorated arborisation, neuritic outgrowth, and neuronal migration. Furthermore, decreased moesin is the second F-actin bundling protein, besides drebrin, that is manifold reduced in fetal DS brain.

Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry.

Rett syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the methyl-CpG-binding protein 2 (MeCP2). A major paradox in the pathogenesis of RTT is how mutations in ubiquitously transcribed MECP2 result in a phenotype specific to the central nervous system (CNS) during postnatal development. To address this question, we have used a novel approach for quantitating the level and distribution of wild-type and mutant MeCP2 in situ by immunofluorescence and laser scanning cytometry. Surprisingly, cellular heterogeneity in MeCP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression (MeCP2(hi)) and the remainder exhibiting low expression (MeCP2(lo)). MeCP2 expression was significantly higher in CNS compared with non-CNS tissues of human and mouse by automated quantitation of MeCP2 on multiple tissue arrays. Quantitative localization of MeCP2 expression phenotypes in normal human brain showed a mosaic, but distinct, distribution pattern, with MeCP2(hi) neurons highest in layer IV of the cerebrum and MeCP2(lo )neurons highest in the granular layer of the cerebellum. In female RTT brains, MECP2 mutant-expressing cells were identified as cells negative for the MeCP2 C-terminal epitope. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MeCP2 expression with N-terminal-specific anti-MeCP2. These results demonstrate a CNS-specific cellular phenotype of MeCP2 high expression and suggest that MECP2 mutations in RTT are only manifested in MeCP2(hi) cells. In addition, our results demonstrate the power of laser scanning cytometry in examining complex cellular phenotypes in disease pathogenesis.

Up-regulation of E2F-1 in Down’s syndrome brain exhibiting neuropathological features of Alzheimer-type dementia

We studied the expression of the apoptosis-related protein, E2F-1, in Down’s syndrome (DS) brains. The immunoreactivity for E2F-1 was detected in the pyramidal neurons of the cerebral cortex from DS brains exhibiting the neuropathological features of dementia of Alzheimer type (DAT), in accordance with the amyloid β protein (Aβ) deposition in the neuron. Therefore, the implication is that Aβ deposition may trigger E2F-1-mediated neuronal apoptosis in DS brains with DAT.

Evidence for apoptosis in the fetal Down syndrome brain.

In Down syndrome, enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic early mental retardation and precocious neurodegeneration of Alzheimer type. Various apoptosis-associated proteins (Bax, Bcl-2, Fas, p53, Hsp70, neuronal apoptosis inhibitory protein-like immunoreactivity) were investigated in four different cortical regions and the cerebellum of one fetal Down syndrome (35 weeks' gestation) postmortem brain sample compared with a control brain sample. The most impressive finding was an at least fivefold elevation of Bax protein together with decreased Bcl-2 values in all Down syndrome cerebral regions investigated. In addition, antiapoptotic, presumably caspase-inhibitory, principles like heat shock protein 70 and neuronal apoptosis inhibitory protein were also reduced. Whereas Fas protein, an important member of receptor-mediated apoptosis, was inconsistently altered, a rather surprising finding was reduced proapoptotic, regulatory protein p53 in four of five regions. The findings are in good agreement with the proposed role of the Bcl-2 protein family in regulating developmental (naturally occurring) apoptotic neuronal death and further suggest that developmental apoptosis may be inappropriately commandeered by so far undefined pathologic processes in Down syndrome.

Effects of the β-Amyloid and Carboxyl-terminal Fragment of Alzheimer's Amyloid Precursor Protein on the Production of the Tumor Necrosis Factor-α and Matrix Metalloproteinase-9 by Human Monocytic THP-1

To explore the direct role of beta-amyloid (Abeta) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT(105)) of amyloid precursor protein on the production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of Abeta. CT(105) elicited a marked increase in TNF-alpha and MMP-9 production in the presence of interferon-gamma in a dose- and time-dependent manner. Similar patterns were obtained with Abeta despite its low magnitude of induction. Autocrine TNF-alpha is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-alpha inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-alpha secretion and subsequent MMP-9 release in response to CT(105) or Abeta. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT(105)-induced effects whereas only PD98059 was effective at reducing Abeta-induced effects. Our results suggest that CT(105) in combination with interferon-gamma might serve as a more potent activator than Abeta in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.

Commentary: Abeta N- Terminal Isoforms: Critical contributors in the course of AD pathophysiology.

The assessment of protein or amino acid variations across evolution allows one to glean divergent features of disease-specific pathology. Within the Alzheimer's disease (AD) literature, extensive differences in Abeta processing across cell lines and evolution have clearly been observed. In the recent past, increased levels of amyloid beta Abeta1-42 have been heralded to be what distinguishes whether one is prone to the development of AD [59]. However, observations in naturally occurring, non-transgenic animals which display a great deal of parenchymal Abeta1-42 (Abeta found within extracellular plaque deposits) and a complete lack ofbeta1-40 within these same Abeta1-42 plaques raise the issue of whether Abetax-42 (Abeta that is truncated or modified at the N- terminus), rather than Abeta1-42, is instead the critical mediator of Abeta production and pathogenesis [47,49]. Distinct ratios of Abeta N-terminal variants (i.e. Abeta1-x, Abeta3-x, Abeta11-x, beta17-x) have been assessed in human amyloid plaques [18,21,40,41,42,47,48,49,52]. Moreover, ratios of specific Abeta N-terminal variants separate naturally occurring, non-transgenic animals which develop abundant levels of Abetax-42 and not Abetax-40 from human AD participants who harbor plaques that contain both the Abetax-42 and Abetax-40 variants [49]. Next, Teller and colleagues have demonstrated the presence of N-terminal truncated soluble 3kD (likely Abeta17-x) and 3.7kD peptides (in addition to 4kD Abeta) well before the appearance of amyloid plaques in Down Syndrome brain [51], indicating an early contribution of thebeta N-terminus to the formation of amyloid pathology. Additional critical facts concerning the major contribution of the Abeta N-terminus in AD pathogenesis include observations which support thatbeta generated by rodent neurons is predominantly truncated at Abeta11-x [13], the major form of APP C-terminal fragments in mice lacking functional PS1 is AbetaPP11-98 [9], beta11-x expression is increased as a function of BACE expression [55], and an interrelationship between presenilin-1 mutations and increased levels of N-terminally truncatedbeta [40]. This commentary highlights current understanding and potential biochemical, pathological, and cell biological contributions of Abeta N-terminal variants implicated during the course of AD pathogenesis. Although the amyloid beta protein precursor (AbetaPP) gene and Abeta are highly conserved across mammalian species, there are species-specific differences. For instance, the primate, guinea pig, canine, and polar bear share an identical Abeta sequence to that observed in human brain while the rat displays a distinct amino acid sequence with substitutions at residues 5 (Arg), 10 (Tyr), and 13 (His) [24,37]. All of these mammals generate Abeta1-42 via cleavage by at least two enzymes, beta (beta-) secretase and gamma (gamma-) secretase (Fig. 1). The enzyme that liberates the N- terminus of the Abeta peptide ('beta-secretase') is also termed BACE (beta-site AbetaPP cleaving enzyme) [55]. Cathepsin D, which accumulates within AD neurons [15], also cleaves at the N-terminal side of the first aspartate residue of amyloid beta [2].beta-secretase activity is necessary in order to initiate 4kD beta1-x formation by cleaving AbetaPP at the N-terminus and results in the release of a soluble 100kD AbetaPP N- terminal fragment and a 12kD membrane bound C-terminal fragment (C99/C100) [55]. The carboxyl-terminus of the Abetapeptide is liberated through cleavage by the enzyme termed gamma-secretase. In the past, potential AD therapeutic strategies have mainly been geared towards gamma-secretase inhibition. However, such strategies alone no longer appear sound as it is clear that the AbetaPP C99/C100 fragment itself, which requires beta-, but not gamma-, secretase cleavage for generation and includes the entire Abeta peptide, is neurotoxic when evaluated in cultured cells [12,30,34]. Thus, gamma-secretase inhibition alone would not preclude the generation of the neurotoxic C99/C100 fragment.

Differential expression of molecular chaperones in brain of patients with Down syndrome.

Heat shock proteins (HSPs) in their molecular capacity as chaperones have been reported to regulate the apoptotic pathway and also play a critical role in protein conformational diseases such as Alzheimer's disease (AD). As all Down syndrome (DS) brains display AD-like neuropathology, neuronal loss in DS was shown to be mediated by apoptosis. We decided to investigate the expression patterns of HSPs in seven brain regions of adults with DS using two-dimensional polyacrylamide gel electrophoresis (2-DE). Following 2-DE, approximately 120 protein spots were successfully identified by matrix-assisted laser desorption/ionization--mass spectrometry (MALDI-MS) followed by quantification of the identified proteins. We unambiguously identified and quantified nine different chaperone proteins. Accordingly, all but three chaperone proteins did exhibit a significant change in expression. HSP 70 RY, heat shock cognate (HSC) 71 and glucose-regulated protein (GRP) 75 showed a significant decrease (P < 0.05) in DS temporal cortex whereas HSP 70.1 and GRP 78 were significantly increased (P<0.05) in cerebellum. Whilst T-complex 1 (TCP-1) epsilon subunit showed a significant decrease (P< 0.05) in parietal cortex, a similar extent of increase (P<0.05) as that observed in cerebellum was obtained in parietal levels of GRP 78. Alpha-crystallin B, HSP 60 and GRP 94 did not show any detectable changes in expression patterns. This report presents the first approach to quantify nine different chaperones simultaneously at the protein level in different brain regions and provides evidence for aberrant chaperone expression patterns in DS. The relevance of this aberrant expression patterns are discussed in relation to the biochemical and neuropathological abnormalities in DS brain.

Complement Association with Neurons and β-Amyloid Deposition in the Brains of Aged Individuals with Down Syndrome

To study the link between β-amyloid (Aβ) and neuroinflammation, we examined the levels of complement as a function of age and extent of Aβ deposition in Down Syndrome (DS) brain. C1q, the first component of the complement cascade, was visualized using immunohistochemistry in the frontal, entorhinal cortex, and hippocampus of 12 DS ranging from 31 to 69 years of age. C1q was consistently associated with thioflavine-S positive Aβ plaques in DS brain and increased with more extensive age-dependent Aβ deposition. In contrast, little or no C1q labeling was associated with diffuse or thioflavine-S negative Aβ deposits. Neurons in the hippocampus and entorhinal cortex, but less frequently in frontal cortex, were C1q positive in DS cases with sufficient neuropathology to have a diagnosis of Alzheimer's disease. C1q-positive neurons were associated with activated microglia. These results provide evidence for Aβ-mediated inflammatory factors contributing to the rapid accumulation of neuropathology in DS brain.

Identification of Amino-Terminally and Phosphotyrosine-Modified Carboxy-Terminal Fragments of the Amyloid Precursor Protein in Alzheimer's Disease and Down's Syndrome Brain

The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered β-amyloid (Aβ) precursors as well as molecular species possibly amyloidogenic and neurotoxic by themselves in vitro or in animal models. The CTF's role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed brain extracted CTFs in subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS subjects CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaques deposition in DS. No significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus are the direct precursors of similarly N-terminally modified Aβ peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated Aβ peptides are formed directly at β-secretase level and not through a progressive proteolysis of full-length Aβ1-40/42. (iii) Among the differently cleaved CTFs, only the 22- and 12.5-kDa CTF polypeptides are tyrosine phosphorylated in both AD and control brain while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that APP and CTFs may be involved in different pathways depending on their length and sequences. This study provides evidence that CTFs constitute in human brain a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.

Alteration of gene expression in Down's syndrome (DS) brains: its significance in neurodegeneration.

Several groups have reported pro-apoptotic alteration of gene expression in Down's syndrome (DS) brains. Aged DS brains manifest a similar neuropathology to Alzheimer's disease (AD), including the presence of senile plaques (SP) and neurofibrillary tangles (NFT). Although it is controversial if neurodegenerative processes play a pathological role in DS brains, evidence such as cortical neurons from fetal DS brains showing vulnerability to cell death when compared with neurons from control subjects supports this point of view. In this chapter, we review the reports that demonstrate pro-apoptotic alteration of gene expression in DS brains. In addition to the pathogenic genes on chromosome 21, such as amyloid precursor protein (APP) and CuZn-superoxide dismutase (SOD1), other genes which associate with p53, or with processes for protein folding have been frequently found.

Reduction of nucleoside diphosphate kinase B, Rab GDP-dissociation inhibitor beta and histidine triad nucleotide-binding protein in fetal Down syndrome brain.

Information on the various factors leading to impairments in the developing brain of fetal Down Syndrome patients is limited to few histological reports. We therefore attempted to describe expression levels of proteins in brain using the proteomic technique of two-dimensional electrophoresis with subsequent mass spectroscopical identification of protein spots and quantification with specific software. Cortical tissue was obtained from autopsy of human fetal abortus. Protein levels of GTP-binding nuclear protein ran, guanine nucleotide-binding protein g(o), alpha subunit 2, guanine nucleotide-binding protein g(i)/g(s)/g(t) beta subunit 1, -beta subunit 2, guanine nucleotide-binding protein beta subunit 5, nucleoside diphosphate kinase A, nucleoside diphosphate kinase B, Rab GDP-dissociation inhibitor beta, Rho GDP-dissociation inhibitor 1, biphosphate 3'-nucleotidase, small glutamine-rich tetra-tricopeptide repeat-containing protein and histidine triad nucleotide-binding protein were studied. Quantification revealed statistically significant reduced levels of nucleoside diphosphate kinase B, Rab GDP-dissociation inhibitor beta and histidine triad nucleotide-binding protein in fetal DS brain as compared to controls. We conclude that in early prenatal life proteins involved in neural differentiation, migration and synaptic transmission are impaired in DS cortex. These results may help to understand the abundant mechanisms leading to abnormalities in the wiring, structure and function of DS brain.

Expression of the multidrug resistance P glycoprotein (Pgp) and multidrug resistance associated protein (MRP1) in Down syndrome brains.

Transport by ATP-dependent efflux pumps such as P glycoprotein (Pgp) and multidrug resistance associated protein (MRP), encoded by multidrug resistant (MDR) associated genes, is an increasingly recognized mechanism by which cells maintain substrate homeostasis and evade drug therapy. Pgp and MRP are members of the so-called ATP binding cassette (ABC) transporters superfamily, which are associated with many biological processes in both prokaryotes and eukaryotes, as well as clinical problems. The observation of upregulated sequences that are homologous to the Mycobacterium smegmatis phage resistance (mpr) gene and putative ABC transporters subunits in fetal Down syndrome (DS) using the gene hunting technique, subtractive hybridization formed the Rationale for this study. The expression of Pgp and MRP1 is therefore investigated in different brain regions of controls and adult DS patients with western blot technique. No apparent changes were observed between controls and DS in levels of Pgp in all brain regions examined. By contrast, MRP1 detection using the rat monoclonal antibody (MRPr1) produced a significant elevation in DS temporal cortex (P < 0.01) and parietal cortex (P < 0.05). Although MRP1 detected with the mouse monoclonal antibody (MRPm6) tended to increase in most of the regions of DS brain, it failed to reach significance level. Age or postmortem interval did not correlate with protein levels in both controls as well as DS. Taken together, the current data provide evidence for the presence of MDR related pumps in different regions of the human brain. In addition, overexpression of MRP1 in DS brain may have some relevance to the disorder either by deranging substrate homeostasis or limiting drug access.

Aberrant expression of dihydropyrimidinase related proteins-2,-3 and -4 in fetal Down syndrome brain.

Pathfinding of growing axons to reach their target during brain development is a subtle process needed to build up contacts between neurons. Abnormalities in brain development in Down Syndrome (DS) are described in a couple of morphological reports but the molecular mechanisms underlying abnormal wiring in fetal DS brain are not yet elucidated. We therefore performed a study using the proteomic approach to show differences in protein levels involved in the guidance of axons between control and DS brain in early prenatal life. Proteins obtained from autopsy of human fetal abortus were applied on 2-dimensional gel, identified and quantified. We quantified 5 members of the semaphorin/collapsin family, the dihydropyrimidinase related proteins 1-4 and the collapsin response mediator protein-5 (CRMP-5) in 8 DS and 7 control cortex samples. DRP-1 and CRMP-5 levels were comparable in the control and DS samples. Evaluation of DRP-2, DRP-3 and DRP-4 revealed significantly decreased levels of 2 of the 15 spots assigned to DRP-2 and increased levels of one spot assigned to DRP-3 and increased DRP-4 in DS brain. We conclude that as early as from the 19th week of gestation pathfinding cues of the outgrowing axons are impaired in DS. These findings may help to elucidate mechanisms leading to abnormalities in neural migration of DS brain.

Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains.

Defects of mitochondrial electron transport enzymes have been implicated in the pathogenesis of several neurodegenerative diseases. In previous work, we reported decreased protein levels of mitochondrial electron transport enzyme subunits in adult brain with Down syndrome (DS). However it is not clear whether cellular damage due to mitochondrial defects in brain of DS fetus begins in utero. Here we investigated the protein levels of mitochondrial electron transport enzymes in fetal DS brain using the proteomic technologies. Two-dimensional (2-D) gel electrophoresis, matrix-assisted laser desorption ionization mass spectroscopy (MALDI-MS) and specific software for quantification were used. The protein levels of complex I 30-kDa subunit were significantly decreased in cerebral cortex of fetal DS brain. We conclude that decreased mitochondrial electron transport enzyme subunits in fetal DS brains could contribute to the impaired energy and free radical metabolism affecting brain development in DS fetus. Furthermore, the defects of mitochondrial electron enzymes shown in adult DS brains could begin in utero and continue during the life span of the individual with DS.

Increased protein levels of heterogeneous nuclear ribonucleoprotein A2/B1 in fetal Down syndrome brains.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are predominantly nuclear RNA-binding proteins that form complexes with RNA polymerase II transcripts. These proteins play pivotal roles in transcription, pre-mRNA processing in the nucleus, cytoplasmic mRNA translation and its turnover. In addition, hnRNPs have been shown to be essential for embryonic development of Drosophila. Here we studied the protein levels of hnRNPs (A2/B1, H and H') in fetal brain with Down syndrome (DS; n = 5) compared to controls (n = 7). We used two-dimensional (2-D) gel electrophoresis, matrix-assisted laser desorption ionization mass spectroscopy (MALDI-MS) and specific software for quantification. hnRNP A2/B1 was significantly increased in fetal DS brain (13.52+/-4.50) compared to controls (9.16+/-1.35), but both hnRNP H and H' were unchanged. Increased hnRNP A2/B1 in fetal DS brain may represent high activity of RNA processing such as RNA trafficking and telomere protection, and/or it could contribute to abnormal development of DS brains. Furthermore, comparable expression of hnRNP H and H' suggest a specific upregulation of hnRNP A2/B.

Deficient brain snRNP70K in patients with Down syndrome

The small nuclear ribonucleoprotein 70K (snRNP 70K; U1-70 kDa) is an integral part of the spliceosome, a large RNA-protein complex catalyzing the removal of introns from nuclear pre-mRNA. snRNP is one of the best-studied essential subunits of snRNPs, is highly conserved and its inactivation was shown to result in complete inhibition of splicing. Applying subtractive hybridization, we found a sequence with 100% identity to snRNP absent in fetal Down syndrome (DS) brain. This observation made us determine snRNP-mRNA steady-state levels and protein levels in brains of adult patients with DS. snRNP-mRNA and protein levels of five individual brain regions of DS and controls each, were determined by blotting techniques. snRNP-mRNA steady state levels were significantly decreased in DS brain. Performing Western blots with monoclonal and human antibodies, snRNP protein levels were decreased in several regions of DS brain, although one monoclonal antibody did not reveal different snRNP-immunoreactivity. Although decreased snRNP-protein could be explained by decreased mRNA-steady state levels, another underlying mechanism might be suggested: snRNP is one of the death substrates rapidly cleaved during apoptosis by interleukin-1-beta-converting enzyme-like (ICE) proteases, which was well-documented by several groups. As apoptosis is unrequivocally taking place in DS brain leading to permanent cell loses, decreased snRNP-protein levels may therefore reflect decreased synthesis and increased apoptosis-related proteolytic cleavage.

Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure.

Information on fetal brain in Down Syndrome (DS) is limited and there are only few histological, mainly anecdotal reports and no systematic study on the wiring of the brain in early prenatal life exists. Histological methods are also hampered by inherent problems of morphometry of neuronal structures. It was therefore the aim of the study to evaluate neuronal loss, synaptic structures and dendritic spines in the fetus with Down Syndrome as compared to controls by biochemical measurements. 2 dimensional electrophoresis with subsequent mass spectroscopical identification of spots and their quantification with specific software was selected. This technique identifies proteins unambiguously and concomitantly on the same gel. Fetal cortex samples were taken at autopsy with low post-mortem time, homogenized and neuron specific enolase (NSE) determined as a marker for neuronal density, the synaptosomal associated proteins alpha SNAP [soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein], beta SNAP, SNAP 25 and the channel associated protein of synapse 110 (chapsyn 110) as markers for synaptosomal structures and drebrin (DRB) as marker for dendritic spines. NSE, chapsyn 110 and beta SNAP were comparable in the control fetus panel and in Down Syndrome fetuses. Drebrin was significantly and remarkably reduced and not even detectable in several Down Syndrome brain samples. Quantification of SNAP 25 revealed significantly reduced values in DS cortex and alpha SNAP was only present in half of the DS individuals. We conclude that at the time point of about 19 weeks of gestation (early second trimester) no neuronal loss can be detected but drebrin, a marker for dendritic spines and synaptosomal associated proteins alpha SNAP and SNAP 25 were significantly reduced indicating impaired synaptogenesis. Early dendritic deterioration maybe leading to the degeneration of the dendritic tree and arborization, which is a hallmark of Down Syndrome from infancy.

The developmental and aging changes of Down's syndrome cell adhesion molecule expression in normal and Down's syndrome brains.

We studied the expression of Down's syndrome cell adhesion molecule (DSCAM) in Down's syndrome (DS) and control brains, using antisera against peptide fragments of DSCAM. On Western blots of human, mouse and rat brain homogenates, the antisera recognized a product at approximately 200 kDa. In the brain of a 2-year-old patient with DS, Western blotting revealed an overexpression of DSCAM compared to an age-matched control. Immunohistochemistry demonstrated DSCAM in the cerebral and cerebellar white matter of both control and DS subjects, in accordance with the temporal and spatial sequence of myelination. In DS brains, immunoreactivity for DSCAM, compared to that for controls, was enhanced in the Purkinje cells at all ages, and in the cortical neurons during adulthood. In demented DS patients, DSCAM immunoreactivity was observed in the core and periphery of senile plaques. The pattern of DSCAM expression suggests that it may play a role as an adhesion molecule regulating myelination. The overexpression of DSCAM may also play a role in the mental retardation and the precocious dementia of DS patients, although the mechanism of neuronal dysfunction is undetermined.

Phospholipid composition and levels are altered in down syndrome brain

Phospholipid composition (mol %) and levels (nmol/mg protein) were determined in postmortem frontal cortical and cerebellar gray matter from older Down Syndrome (DS) patients (age range 38–68 years) and from control subjects. Neither DS nor control tissue exhibited any age-dependent alteration in phospholipid composition or levels. Total phospholipid content was significantly reduced approximately 20% in DS frontal cortex and cerebellum relative to these regions in control tissue. Individual phospholipid levels were also reduced in DS frontal cortex and cerebellum, including a specific 37% decrease in phosphatidylinositol (PtdIns) and a nearly 35% decrease in ethanolamine plasmalogen. Because of the large decrease in phospholipid content in DS brain, the cholesterol/phospholipid ratio was calculated for each group. There was no significant difference in this ratio between groups, indicative of compensatory changes to keep the cholesterol/phospholipid ratio constant. Despite the large changes in DS brain phospholipid levels, significant changes in composition were limited to a 18% decrease in PtdIns mol % and a 22% increase in the mol % of sphingomyelin. These results suggest either a decrease in membrane phospholipids due to a loss of dendrites and dendritic spines, or a general defect in brain lipid metabolism in older DS subjects. The proportionally greater alterations in PtdIns and PlsEtn levels, indicate that the metabolism of these two phospholipids was affected to a greater extent than the other phospholipids. Further, because these changes are found in both the frontal cortical and cerebellar gray matter, they likely are related to the Down syndrome condition rather than to Alzheimer neuropathology.

Expression of two novel β-secretase-candidate aspartyl proteases in Alzheimer's disease and down syndrome brain

Expression of two novel β-secretase-candidate aspartyl proteases in Alzheimer's disease and down syndrome brain