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1.
Individuals with Down syndrome (DS) develop most neuropathological hallmarks of Alzheimer's disease early in life, including loss of cholinergic markers in the basal forebrain. Ts65Dn mice, an animal model of DS, perform poorly on tasks requiring spatial memory and also exhibit basal forebrain pathology beginning around 6 months of age. We evaluated memory as well as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein levels in basal forebrain, frontal cortex, hippocampus, and striatum in Ts65Dn mice at the age when cholinergic degeneration is first observed, and compared values to normosomic controls. Six-month-old Ts65Dn mice exhibited impairments in working and reference memory as assessed on a water radial-arm maze. The working memory deficit was related to the inability of Ts65Dn mice to successfully sustain performance as the working memory load increased. Coupled with cognitive performance deficiencies, Ts65Dn mice also exhibited lower frontal cortex BDNF protein levels than controls. Further, BDNF levels were negatively correlated with working memory errors during the latter portion of testing in Ts65Dn mice, thereby suggesting that lower BDNF protein levels in the frontal cortex may be associated with the observed working memory impairment.  相似文献   

2.
Ts65Dn mice are partially trisomic for a segment of murine chromosome 16 similar to the gene segment on human chromosome 21 affected in Down's syndrome (DS). These animals display cognitive deficits, neurochemical imbalances, and cholinergic degeneration resembling alterations in DS and early onset Alzheimer's disease. The loss of basal forebrain cholinergic phenotype in Ts65Dn mice begins at approximately 6 months of age and may be due to an improperly functioning neurotrophic system. We compared 4 and 6 month-old Ts65Dn mice in a water-escape radial-arm maze task to investigate working and reference memory before and after the reported onset of cholinergic decline. Both 4 and 6 month-old Ts65Dn mice exhibited impaired performance compared to age-matched controls. However, the younger Ts65Dn mice displayed the capability to learn all working and reference memory measures, while the older Ts65Dn mice did not. Ts65Dn mice failed to maintain performance as working memory load increased, and the ability to handle an increasing working memory load also diminished with age. Collectively, these data suggest that major alterations in cognitive function occur in Ts65Dn mice between the ages of 4 and 6 months.  相似文献   

3.
Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer's disease (AD). Chronic treatments using memantine in animal models of Alzheimer's disease show disease-modifying effects and suggest a potential neuroprotective function. The present study assessed the effects of both short- and long-term memantine treatment in a mouse model of Down syndrome (DS), the Ts65Dn mouse. The Ts65Dn mouse contains a partial trisomy of murine chromosome 16, and exhibits hippocampal-dependent memory deficits, as well as progressive degeneration of basal forebrain cholinergic neurons (BCFNs). Ts65Dn mice were treated with memantine for a period of 6 months, beginning at 4 months of age. At the end of treatment the mice underwent memory testing using novel object recognition and water radial arm maze tasks, and then histologically analyzed for markers of neurodegeneration. Memantine treatment improved spatial and recognition memory performance in the Ts65Dn mice, though not to the level of normosomic littermate controls. Despite these memory improvements, histological analysis found no morphological signs of neuroprotection of basal forebrain cholinergic or locus coeruleus neurons in memantine-treated Ts65Dn mice. However, memantine treatment of Ts65Dn mice gave rise to elevated brain-derived neurotrophic factor expression in the hippocampus and frontal cortex, suggesting a mechanism of behavioral modification. Thus, our findings provide further evidence for memory facilitation of memantine, but suggest pharmacological rather than neuroprotective effects of memantine both after acute and chronic treatment in this mouse model.  相似文献   

4.
5.
Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies.  相似文献   

6.
Individuals with Down syndrome (DS) develop the pathological hallmarks of Alzheimer's disease at an early age, later followed by memory decline and dementia. Women with DS are twice as likely to undergo early menopause, and levels of estradiol correlate with onset of cognitive decline in these women. We have demonstrated that a mouse model of DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), develop a significant deficit in both reference and working memory as young adults (6-10 months of age), coupled with phenotypic loss of cholinergic neurons in the basal forebrain and altered growth factor levels. 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. The density of the dendritic marker Map2 was significantly decreased in the hippocampal formation of middle-aged trisomic mice (9-15 months old), and the density of cholinergic neurites (acetylcholinesterase [AChE] histochemistry) was also decreased in specific layers of the hippocampus. Treatment with 17beta-estradiol alleviated the decreases in Map2 and AChE staining, but had no effect on full-length APP levels in the hippocampus. In contrast, a main effect of treatment on APP levels in the striatum was noted, with significant elevations observed in controls and trisomics. These findings demonstrate that estrogen can alleviate deficits in cholinergic and dendritic elements in the hippocampal formation and further strengthens the rationale to explore estrogen replacement therapy in women with DS.  相似文献   

7.
Mice with segmental trisomy of chromosome 16 (Ts65Dn) have been used as a model for Down's syndrome. These mice are born with a normal density of basal forebrain cholinergic neurons but, like patients with Down's syndrome, undergo a significant deterioration of these neurons later in life. The time course for this degeneration of cholinergic neurons has not been studied, nor is it known if it correlates with the progressive memory and learning deficits described. Ts65Dn mice that were 4, 6, 8, and 10 months old were sacrificed for evaluation of basal forebrain morphology. Separate groups of mice were tested on visual or spatial discrimination learning and reversal. We found no alterations in cholinergic markers in 4-month-old Ts65Dn mice, but thereafter a progressive decline in density of cholinergic neurons, as well as significant shrinkage of cell body size, was seen. A parallel loss of staining for the high-affinity nerve growth factor receptor, trkA, was observed at all time points, suggesting a biological mechanism for the cell loss involving this growth factor. Other than transient difficulty in learning the task requirements, there was no impairment of trisomic mice on visual discrimination learning and reversal, whereas spatial learning and reversal showed significant deficits, particularly in the mice over 6 months of age. Thus, the loss of ChAT-immunoreactive neurons in the basal forebrain was coupled with simultaneous deficits in behavioral flexibility on a spatial task occurring for the first time around 6 months of age. These findings suggest that the loss of cholinergic function and the simultaneous decrease in trkA immunoreactivity in basal forebrain may directly correlate with cognitive impairment in the Ts65Dn mouse Copyright 2000 Academic Press.  相似文献   

8.
Lorenzi HA  Reeves RH 《Brain research》2006,1104(1):153-159
Ts65Dn, a well-characterized animal model for Down syndrome, has three copies of the distal end of mouse chromosome 16 and therefore has segmental trisomy for orthologs for nearly half of the genes located on human chromosome 21. Ts65Dn mice have learning and memory impairments, especially in tasks involving the hippocampus. Previous studies have shown that older adult Ts65Dn mice have structural abnormalities in the hippocampus including fewer granule cells in dentate gyrus and more pyramidal cells in the CA3 subfield of cornus ammonis. However, it is not clear whether those changes are secondary to the age-related neurodegeneration of the basal forebrain cholinergic neurons that project to the hippocampus or if they originate earlier during hippocampal development. To address this question, we performed a quantitative study of the hippocampal volume and the numbers of granule cell and pyramidal neurons in young (postnatal day 6, P6) and adult (3-month-old) mice using the optical fractionator method. At P6, Ts65Dn mice had 20% fewer granule cells in dentate gyrus than did euploid littermates. Similarly, compared to euploid, P6 trisomic mice showed an 18% reduction in mitotic cells in the granule cell layer and the hilus, where granule cell precursors divide to generate the internal granule cell layer. Granule cell hypocellularity persists in 3-month-old Ts65Dn mice before the onset of cholinergic atrophy. The hypocellularity seen in the trisomic adult hippocampus originates early in development and may contribute to specific cognitive deficits in these mice.  相似文献   

9.
Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age‐related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 months of age. Ts65Dn dams were maintained on a choline‐supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75‐neurotrophin receptor (p75NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn‐unsupplemented mice displayed region‐ and immunolabel‐dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal‐diet choline supplementation attenuates some of the genotype‐dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. J. Comp. Neurol. 522:1390–1410, 2014. © 2013 Wiley Periodicals, Inc.  相似文献   

10.
The Ts65Dn mouse is the most studied and genetically the most complete animal model of Down syndrome (DS) available. These mice display many DS-like features, including performance deficits in different behavioral tasks, motor dysfunction, and age-dependent loss of cholinergic markers in the basal forebrain. At present, the only robust data demonstrating a behavioral deficit potentially associated with learning and memory in Ts65Dn mice less than 6 months old have come from studies that used some variation of the Morris water maze task. However, the specific features of the water maze deficits seen in these animals are still poorly defined. This study is an initial attempt to bridge this knowledge gap. We investigated three major factors potentially influencing the performance of Ts65Dn mice in the water maze: (1) order in which the test is executed; (2) age of the animals; and (3) levels of aversiveness associated with the test. Measurements of plasma corticosterone levels and core body temperature after swimming were also carried out in additional subsets of mice. Overall, we found that the behavioral phenotype of Ts65Dn mice was milder than previously described in the literature. Additionally, Ts65Dn mice were significantly more responsive to potential stressors and more prone to swim-induced hypothermia than euploid control animals. More studies are needed to tease out further the potential effects of confounding factors on the performance of Ts65Dn mice.  相似文献   

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