Systemic pathology in aged mouse models of Down's syndrome and Alzheimer's disease (original) (raw)
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Individuals with Down syndrome develop b-amyloid deposition characteristic of early-onset Alzheimer’s disease (AD) in midlife, presumably because of an extra copy of the chromosome 21-located amyloid precursor protein (App) gene. App mRNA and APP metabolite levels were assessed in the brains of Ts65Dn mice, a mouse model of Down syndrome, using quantitative PCR, western blot analysis, immunoprecipitation, and ELISAs. In spite of the additional App gene copy, App mRNA, APP holoprotein, and all APP metabolite levels in the brains of 4-month-old trisomic mice were not increased compared with the levels seen in diploid littermate controls. However starting at 10 months of age, brain APP levels were increased proportional to the App gene dosage imbalance reflecting increased App message levels in Ts65Dn mice. Similar to APP levels, soluble amino-terminal fragments of APP (sAPPa and sAPPb) were increased in Ts65Dn mice compared with diploid mice at 12 months but not at 4 months of age. Brain levels of both Ab40 and Ab42 were not increased in Ts65Dn mice compared with diploid mice at all ages examined. Therefore, multiple mechanisms contribute to the regulation towards diploid levels of APP metabolites in the Ts65Dn mouse brain.
Proceedings of the National Academy of Sciences, 1988
Mouse trisomy 16 has been proposed as an animal model of Down syndrome (DS), since this chromosome contains homologues of several loci from the q22 band of human chromosome 21. The recent mapping of the defect causing familial Alzheimer disease (FAD) and the locus encoding the Alzheiner amyloid (3 precursor protein (APP) to human chromosome 21 has prompted a more detailed examination of the extent of conservation of this linkage group between the two species. Using anonymous DNA probes and cloned genes from Abbreviations: DS, Down syndrome; FAD, familial Alzheimer disease; RFLP, restriction fragment length polymorphism; SDP, strain distribution pattern; CI, confidence interval; RI, recombinant inbred.
Neuroscience Letters, 2010
Human Down syndrome (DS) represents the most frequent cause of mental retardation associated to a genetic condition. DS also exhibits a characteristic early onset of neuropathology indistinguishable from that observed in Alzheimer's disease (AD), namely the deposition of the -amyloid peptide. Early endosomal dysfunction has been described in individuals with DS and AD, suggesting an important role of this subcellular compartment in the onset and progression of the pathology. On the other hand, cholesterol activates the amyloidogenic processing pathway for the amyloid precursor protein, and the lipoprotein receptor-related peptide interacts with the -amyloid peptide. In the present work, using cell lines derived from the cortex of both normal and trisomy 16 mice (Ts16), an animal model of DS, we showed that the application of exogenous -amyloid has cytotoxic effects, expressed in decreased viability and increased apoptosis. Supplementation of the culture media with cholesterol associated to lipoprotein increased cell viability in both cell lines, but apoptosis decreased only in the normal cell line. Further, intracellular -amyloid content was elevated in trisomic cells following cholesterol treatment, with higher values in the trisomic cell line. Immunocytochemical detection showed intracellular accumulation of exogenous -amyloid in Rab4-positive compartments, which are known to be associated to endosomal recycling. The results suggest that the intracellular -amyloid pool plays a central role in apoptosis-mediated cell death in the trisomic condition.
In vivo and ex vivo analyses of amyloid toxicity in the Tc1 mouse model of Down syndrome
Journal of psychopharmacology (Oxford, England), 2018
The prevalence of Alzheimer's disease is increased in people with Down syndrome. The pathology appears much earlier than in the general population, suggesting a predisposition to develop Alzheimer's disease. Down syndrome results from trisomy of human chromosome 21, leading to overexpression of possible Alzheimer's disease candidate genes, such as amyloid precursor protein gene. To better understand how the Down syndrome context results in increased vulnerability to Alzheimer's disease, we analysed amyloid-β [25-35] peptide toxicity in the Tc1 mouse model of Down syndrome, in which ~75% of protein coding genes are functionally trisomic but, importantly, not amyloid precursor protein. Intracerebroventricular injection of oligomeric amyloid-β [25-35] peptide in three-month-old wildtype mice induced learning deficits, oxidative stress, synaptic marker alterations, activation of glycogen synthase kinase-3β, inhibition of protein kinase B (AKT), and apoptotic pathways as ...
The Use of Mouse Models for Understanding the Biology of Down Syndrome and Aging
Down syndrome is a complex condition caused by trisomy of human chromosome 21. The biology of aging may be different in individuals with Down syndrome; this is not well understood in any organism. Because of its complexity, many aspects of Down syndrome must be studied either in humans or in animal models. Studies in humans are essential but are limited for ethical and practical reasons. Fortunately, genetically altered mice can serve as extremely useful models of Down syndrome, and progress in their production and analysis has been remarkable. Here, we describe various mouse models that have been used to study Down syndrome. We focus on segmental trisomies of mouse chromosome regions syntenic to human chromosome 21, mice in which individual genes have been introduced, or mice in which genes have been silenced by targeted mutagenesis. We selected a limited number of genes for which considerable evidence links them to aspects of Down syndrome, and about which much is known regarding their function. We focused on genes important for brain and cognitive function, and for the altered cancer spectrum seen in individuals with Down syndrome. We conclude with observations on the usefulness of mouse models and speculation on future directions. a disruptive behavioral disorder, such as attention deficit hyperactivity disorder, conduct/oppositional disorder, or aggressive behavior. About 25.6% of adults have a psychiatric disorder, most frequently depression or aggressive behavior. People with DS have a higher incidence of autism. By the fifth decade of life, neuropathological changes typical of Alzheimer's disease (AD) usually develop. Clinical signs and symptoms of AD are seen in 75% of people over 60 years of age. These are usually seizures, changes in personality, focal neurological signs, apathy, and loss of conversational skills .
Brain and Development, 1997
We studied immunohistochemically the expression of B-amyloid precursor protein (APP) in the frontal lobes of 18 Down syndrome (DS) patients (20 gestation weeks (GW) to 50 years) and 15 controls (17 GW to 50 years) using six purified antibodies against the secretory forms (N-terminal, N-Amy and Amy540), the Kunitz-type protease inhibitor (KPI) domain, residues 1-28 of/3 protein (Affi28), and the carboxyl-terminal fragment (Ac) of APP. In the cortex of fetuses, neonates and infants, immunoreactivity for N-Amy and Ac was observed in both neurons and glial ceils, and that for Affi28 in glial cells in the subpial layer in both DS patients and controls suggesting the functioning role of APP as a growth factor. This immunoreactivity disappeared in childhood and reappeared in adulthood in only DS patients. The earlier reappearance of those in DS patients from a young adult age than in normal controls may result from a gene dosage effect, since APP is encoded on chromosome 21. The N-Amy, Amy540, Affi28 and Ac immunoreactivity in glial cells in the developing white matter in the both DS patients and controls may be associated with myelination glia. Immunoreactivity for KPI was noted on the tunica media of the arteries from the neonatal period to adulthood in only DS patients. In senile plaques in DS patients, N-terminal and Affi28 immunoreactivity became detectable at the age of 32 years. N-terminal immunoreactivity in the senile plaques was noted along the periphery of the senile plaques, while that for Affi28 was around the amyloid core. Thus, each fragment of APP exhibited a different localization and time course of immunohistochemical expression. The results indicated that APP plays a role in neuronal development and that its earlier reappearance in adult DS patients is associated with the regeneration process related to aging.
Immortalized Neural Cells from Trisomy 16 Mice as Models for Alzheimer's Disease
Annals of the New York Academy of Sciences, 1996
The trisomy 16 mouse (Ts16) is a general accepted animal model for both Downs syndrome (DS) and Alzheimer's Disease (AD). However, the efficacy of this model is severely hampered by the fact that Ts16 is lethal after about 18-20 days of gestation. Chimeras, long-term tissue culture and neural transplantation of Ts16 material have previously been used to overcome this limitation presented by death in utero of the Ts16. In this paper we describe a new strategy to overcome this limitation, i.e. immortalization of primary cells from Ts16 mice with retrovirus-mediated gene transfer of a temperature sensitive immortalizing oncogene. By this method we have obtained a total of 21 stable cell lines from Ts16 hippocampus, Ts16 cortex, normal hippocampus, and normal cortex. So far, two of the cell lines have been karyotyped and as expected, the cell line immortalized from Ts16 embryos has retained three copies of chromosome 16. We are currently characterizing these cell lines with respect to expression of APP, T-antigen, Nestin, GFAP, NF and Map-2. Moreover, the processing and secretion of APP fragments are being investigated by immunoblotsing. In summary, we have immortalized CNS cells from Ts16 mice and we expect that these cell Lines will be useful as in vitm and in vim models for studying various aspects of the pathology of Alzheimer's disease.
Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP
Brain : a journal of neurology, 2018
Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease p...