Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

Lockrow, Jason; Prakasam, A.; Huang, Peng; Bimonte‐Nelson, Heather A.; Sambamurti, Kumar; Granholm, Ann Charlotte

doi:10.1016/j.expneurol.2008.11.021

Cited by 114 publications

(114 citation statements)

References 81 publications

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“…In previous studies other authors have observed an increase of calbindin D-28k immunoreactive interneurons in 30 days old animals [43]; however, another study using 10 months old animals reflects a reduction in the density of this subpopulation of interneurons in the hippocampus [41,42]. Our animals are young adults (4-5 months old) and they present a higher density of calbindin D-28k neurons in the hippocampus than controls.…”

Section: Interneurons Expressing Calcium Binding Proteinssupporting

confidence: 37%

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

et al. 2014

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Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

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Section: Interneurons Expressing Calcium Binding Proteinssupporting

confidence: 37%

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

et al. 2014

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“…Staining density, measured with a gray scale ranging from 0 to 256, was obtained when background staining was subtracted from mean staining intensities for each section. Mean intensity values were averaged per animal and then analyzed for statistical significance using GraphPad Prism version 6 (GraphPad Software, La Jolla, CA) as described previously [12,40,41].…”

Section: Densitometrymentioning

confidence: 99%

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Ledreux

Wang

Schultzberg

et al. 2016

Behavioural Brain Research

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High fat diets have detrimental effects on cognitive performance, and can increase oxidative stress and inflammation in the brain. The aging brain provides a vulnerable environment to which a high fat diet could cause more damage. We investigated the effects of a high fat/high cholesterol (HFHC) diet on cognitive performance, neuroinflammation markers, and phosphorylated Tau (p-Tau) pathological markers in the hippocampus of Young (4-month old) versus Aged (14-month old) male rats. Young and Aged male Fisher 344 rats were fed a HFHC diet or a normal control diet for 6 months. All animals underwent cognitive testing for 12days in a water radial arm maze to assess spatial and working reference memory. Hippocampal tissue was analyzed by immunohistochemistry for structural changes and inflammation, and Western blot analysis. Young and Aged rats fed the HFHC diet exhibited worse performance on a spatial working memory task. They also exhibited significant reduction of NeuN and calbindin-D28k immunoreactivity as well as an increased activation of microglial cells in the hippocampal formation. Western blot analysis of the hippocampus showed higher levels of p-Tau S202/T205 and T231 in Aged HFHC rats, suggesting abnormal phosphorylation of Tau protein following the HFHC diet exposure. This work demonstrates HFHC diet-induced cognitive impairment with aging and a link between high fat diet consumption and pathological markers of Alzheimer's disease.

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“…The evidence as to whether Ts65Dn mice have elevated levels of oxidative stress has been very limited. Now, oxidative stress has been demonstrated in the brains of Ts65Dn mice, and long-term treatment with vitamin E seems to reverse the elevated oxidative stress, to delay the memory loss, to preserve markers of cholinergic cell loss, and to preserve hippocampal morphology in these mice (Lockrow et al 2009). There is also some evidence that oxidative stress may be elevated in thymocytes and macrophages of Ts65Dn mice (Paz-Miguel et al 1999).…”

Section: Mouse Models and The Study Of Dsmentioning

confidence: 99%

“…A particularly intriguing set of recent results demonstrates that treatment of mouse models, notably Ts65Dn mice, with a variety of agents, appears to improve learning and memory and perhaps brain structure in these mice (Lockrow et al 2009;Costa et al 2008;Rueda et al 2008;Fernandez et al 2007). So far, these studies have been carried out on adult mice.…”

Section: Possible Therapies For Dsmentioning

confidence: 99%

Molecular genetic analysis of Down syndrome

2009

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Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

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Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

Cited by 114 publications

References 81 publications

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

Detrimental effects of a high fat/high cholesterol diet on memory and hippocampal markers in aged rats

Molecular genetic analysis of Down syndrome

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