Disease relevance of T(16C3-4;17A2)65Dn

• We have generated immortal neuronal cell lines from normal and trisomy 16 (Ts16) mice, a model for Down syndrome (DS) [1].
• Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down's syndrome and related neurodegenerative diseases [2].
• We previously demonstrated that Ts 16 basal forebrain cholinergic neurons (BFCNs) undergo age-related atrophy similar to DS and AD, and now show that a specific neurotrophic factor, nerve growth factor (NGF), acts to reverse Ts 16-induced atrophy of BFCNs and stimulates hypertrophy of these cells [3].
• Abnormal lymphatic development in trisomy 16 mouse embryos precedes nuchal edema [4].
• Perturbation of muscularization has been implicated in the pathogenesis of cardiac malformations in several animal models for congenital heart disease, including the Trisomy 16 mouse and the TGFbeta2 knockout mouse [5].

Psychiatry related information on T(16C3-4;17A2)65Dn

• Transplants of mouse trisomy 16 hippocampus provide a model of Alzheimer's disease neuropathology [6].
• Ts65Dn mice, trisomic for a portion of chromosome 16 segmentally homologous to human chromosome 21, are an animal model for Down's syndrome and related neurodegenerative diseases, such as dementia of the Alzheimer type [2].
• We have utilized an animal model for DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), to study biological events linked to memory loss [7].
• Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation [8].
• Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function [9].

High impact information on T(16C3-4;17A2)65Dn

• The reproducibility of this phenotype among Ts65Dn mice indicates that dosage imbalance for a gene or genes in this region contributes to this impairment [10].
• These abnormalities have similarities with the skeletal anomalies found in trisomy-16 mice and humans with Down's syndrome, in which the gene dosage of Ets2 is increased [11].
• Down syndrome, Alzheimer's disease and the trisomy 16 mouse [12].
• Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing [13].
• Mouse fetuses with trisomy 16 have severe abnormalities of several hematopoietic stem cell and precursor populations [14].

Chemical compound and disease context of T(16C3-4;17A2)65Dn

• To test this hypothesis, we investigated age-dependent changes in neuronal survival and glutamate effects on Ca2+ homeostasis and mitochondrial energy metabolism in cultured hippocampal neurons from diploid and trisomy 16 (Ts16) mice, a model of Down's syndrome [15].
• Brain accumulation of myo-inositol in the trisomy 16 mouse, an animal model of Down's syndrome [16].
• Behavioral and neurobiological markers of Alzheimer's disease in Ts65Dn mice: effects of estrogen [17].
• Diminished glutathione levels cause spontaneous and mitochondria-mediated cell death in neurons from trisomy 16 mice: a model of Down's syndrome [18].
• Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome [19].

Biological context of T(16C3-4;17A2)65Dn

• Genetic homology which exists between human chromosome 21 (HSA 21) and mouse chromosome 16 (MMU 16) has led to the use of mice with trisomy 16 as a model system for studies relevant to DS [20].
• These findings expand the region of HSA 21 with known homology to MMU 16, and provide a genetic basis to suggest that studies of the trisomy 16 mouse, in addition to being relevant to DS, may also clarify the role of abnormal gene expression in AD [20].
• This chromosome confers trisomy for most of the genes in the Chr 16 segment and Ts65Dn mice show many of the phenotypic features characteristic of Down syndrome [21].
• App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome [22].
• Since the gene encoding amyloid precursor protein has been localized to mouse chromosome 16, we also examined the expression of this gene in the brains of mouse embryos with trisomy 16 and trisomy 19 at 15 days of gestation [23].

Anatomical context of T(16C3-4;17A2)65Dn

• Knockdown of amyloid precursor protein normalizes cholinergic function in a cell line derived from the cerebral cortex of a trisomy 16 mouse: An animal model of down syndrome [1].
• In the present report, we employ neural transplantation to study long-term survival and pathogenesis in Trisomy 16 central nervous system tissues [6].
• In addition, degeneration of basal forebrain cholinergic neurons, which was observed in Ts65Dn, was absent in Ts1Cje [24].
• Overexpressing App at high levels in mice did not alter early endosomes, implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype [22].
• These observations further suggest that the trisomy 16-induced neurodegeneration is seemingly due to a lack of neuron supporting factors which are provided by either the metabolic interaction of trisomic graft with surrounding healthy host tissue or by cells of the immune system infiltrating the graft [25].

Associations of T(16C3-4;17A2)65Dn with chemical compounds

• In the present study we examined cholinergic and dendritic markers in the hippocampal formation and levels of the amyloid precursor protein (APP) in different brain regions of Ts65Dn mice treated with estradiol for 60 days [26].
• In cortical cultures of trisomy 16 mouse brain the upregulated metallothionein-I/II fails to respond to H2O2 exposure or glutamate receptor stimulation [27].
• Addition of N-acetyl-l-cysteine to the culture medium reduced the increment of MT-I/II in trisomy 16 cortical cells [27].
• Glutamate evoked an initial NAD(P)H decrease that was found to be extended in Ts16 neurons in comparison to diploid neurons [15].
• In the presence of cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition, NAD(P)H increase was observed in both diploid and Ts16 neurons [15].

Physical interactions of T(16C3-4;17A2)65Dn

• Activator protein-1 DNA binding activation by hydrogen peroxide in neuronal and astrocytic primary cultures of trisomy-16 and diploid mice [28].

Regulatory relationships of T(16C3-4;17A2)65Dn

• All GIRK2 splicing isoforms examined were expressed at higher levels in the Ts65Dn in comparison to the diploid hippocampus [29].

Other interactions of T(16C3-4;17A2)65Dn

• Two animal models of Down syndrome (human trisomy 21) with segmental trisomy for all (Ts65Dn) or part (Ts1Cje) of human chromosome 21-homologous region of mouse chromosome 16 have cognitive and behavioral abnormalities [30].
• In the trisomy 16 mouse, an animal model of DS, we found marked dysregulation of two developmentally regulated genes, App and Prn-p. Dysregulation varied from tissue to tissue and during development in the same tissue [31].
• Furthermore, abnormal PKC activity and an absence of the increase in Akt phosphorylation were demonstrated in the Ts65Dn hippocampus after high-frequency stimulation that induces long-term potentiation [32].
• We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus [33].
• Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid [33].

Analytical, diagnostic and therapeutic context of T(16C3-4;17A2)65Dn

• RNA gel blot analysis and in situ hybridization showed a marked increase in amyloid precursor protein mRNA in the trisomy 16 mouse head and brain when compared with euploid littermates or with trisomy 19 mice [23].
• Western blot analysis showed that MT-I/II was upregulated and the protein carbonyl content was higher in trisomy 16 compared with euploid cultures [27].
• Here we show that restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death [34].
• Cholinergic function of normal neurons was significantly down-regulated by coculture with Ts16 glia [35].
• Denervation of the hippocampus produced a significant increase in the size of Ts 16 cholinergic neurons [36].

References