Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein

Abstract

Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves overexpression of chromosome 21-encoded genes. The gene for amyloid precursor protein (APP), known to be involved in AD pathology, resides on chromosome 21 along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the metabolism of oxygen free radicals. We investigated the consequences of a combined increase in APP and SOD1, in a double-transgenic (tg)-APP-SOD1 mouse. These mice expressed severe impairment in learning, working and long-term memory. Expression of long-term potentiation in hippocampal slices was impaired in both tg-SOD and tg-APP-SOD mice, but not in tg-APP mice, indicating that increased APP by itself did not affect in vitro synaptic plasticity. In tg-APP-SOD mice, membrane-bound high molecular weight APP species accumulated while APP cleavage products did not increase and levels of secreted APP were unchanged. Severe morphological damage, including lipofuscin accumulation and mitochondria abnormalities, were found in aged tg-APP-SOD but not in the other mice. Thus, a combined elevation of the two chromosome 21 genes in tg-APP-SOD mice induced age-dependent alterations in morphological and behavioural functions.

Age‐dependent decreases in mitogen‐stimulation level and RNA content in peripheral blood mononuclear cells of down syndrome patients

“…In fact, overexpression of genes located on chromosome 21, as a result of extra gene load, has been considered a central hypothesis for the explanation of the DS phenotype (17)(18)(19). However, not all genes show the expected 50% increase in expression in DS (18,19) and in mouse model of DS (1,20). Quantifi- cation of the same proteins encoded on chromosome 21 revealed that not all gene products of the DS critical region are overexpressed in DS brain early in life, indicating that the DS phenotype cannot be simply explained by the gene dosage effect hypothesis (18,19,21).…”

Flow cytometric comparison of RNA content in peripheral blood mononuclear cells of down syndrome patients and control individuals

“…In fact, overexpression of genes located on chromosome 21, as a result of extra gene load, has been considered a central hypothesis for the explanation of the DS phenotype (15). However, not all genes show the expected 50% increase in expression in the DS model of mice, and some genes show age-dependent changes in expression levels (15,16). Quantification of some proteins encoded on chromosome 21 revealed that not all gene products of the DS critical region are overexpressed in DS brain early in life, indicating that the DS phenotype cannot be simply explained by the gene dosage effect hypothesis (17,18).…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…S100B overexpression can also lead to p53 inactivation (Donato, 2003;Gilquin et al, 2010;Leclerc et al, 2010;Lin et al, 2001;Mihara et al, 2003). Finally, similar mechanisms involving mitochondrial dysfunction have been proposed with other HSA21 genes including SOD1 and BATCH1 (Arbuzova et al, 2002;Ferrando-Miguel et al, 2003;Furuta et al, 1995;Harris-Cerruti et al, 2004;Iannello et al, 1999;Lott et al, 2006;Shim et al, 2003). The added, combinatorial effects of these various HSA21 genes in oxidative stress, apoptosis in neurons and neuronal progenitors are not known.…”

“…Inhibit estrogen and glucocorticoid receptors (Cavailles et al, 1995;Gardiner and Costa, 2006;Subramaniam et al, 1999;Teyssier et al, 2003 (Abramov et al, 2004;Arancio et al, 2004;Harris-Cerruti et al, 2004;Howlett and Richardson, 2009;Korbel et al, 2009;Kwak et al, 2010;Kwak et al, 2011;Mori et al, 2010;Prasher et al, 1998;RoveletLecrux et al, 2006;Takuma et al, 2009;Trazzi et al) …”

“…Learning and memory deficits (Furuta et al, 1995;Harris-Cerruti et al, 2004;Iannello et al, 1999;Lott et al, 2006) SYNJ1 PtdIns(4,5)P(2) Synaptic dysfunction, abnormal vesicle trafficking Astrogliagenesis…”