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Anton van Dellen

Publications and source records attributed to Anton van Dellen.

8 recordsLinked to original sources
PubMed2006

Neurogenesis in the R6/1 transgenic mouse model of Huntington's disease: effects of environmental enrichment.

Previous work has demonstrated that the transgenic R6/1 mouse model of Huntington's disease has decreased proliferation of neural precursor cells (NPCs) in the dentate gyrus of the hippocampus. This study therefore examined the survival and differentiation of NPCs in presymptomatic and symptomatic R6/1 mice and the effects of environmental enrichment on these variables. Here it is demonstrated that the survival of bromodeoxyuridine-positive (BrdU+) NPCs in the dentate gyrus is decreased in the transgenic mice. In addition, the number of doublecortin-positive (DCX+) cells is greatly reduced in these mice, as is the total number of new mature neurons, while the proportion of BrdU+ cells differentiating into mature neurons was not significantly different between genotypes. Furthermore, the DCX+ cells in the R6/1 mice had smaller and irregular-shaped somas, shorter neurites, and migrated a shorter distance into the granular cell layer compared with wild-type mice. Older symptomatic mice housed in an enriched environment had an increased number of BrdU+ and DCX+ cells as well as longer neurites and increased migration of DCX+ cells. There was no significant difference between genotypes or environments in the number of BrdU+ cells in the subventricular zone. These results suggest that decreased neurogenesis might be responsible, in part, for the hippocampal deficits observed in these mice and that environmental enrichment produces morphological changes in newborn granule neurons in both wild-type and R6/1 mice, which could underlie some of the beneficial effects of enrichment.

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PubMed2005

Gene-environment interactions, neuronal dysfunction and pathological plasticity in Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. The dynamic mutation that causes the disease is common to numerous other brain disorders, which may share similar pathogenic mechanisms. Much progress has been made in the past decade in understanding how a trinucleotide (CAG) repeat expansion, encoding an expanded polyglutamine tract in the huntingtin protein, induces dysfunction at molecular and cellular levels. The present review integrates various lines of experimental evidence in an attempt to move towards a unifying mechanistic framework, which may explain the pathogenesis of HD, from molecular through to neuronal network and behavioural levels. Recent evidence, using transgenic mouse models, also suggests that environmental factors can modify the onset and progression of HD. The effects of specific environmental manipulations are discussed in the context of gene-environment interactions and experience-dependent plasticity in the healthy and diseased brain, particularly the cerebral cortex.

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PubMed2005

Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.

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PubMed2004

Decreased hippocampal cell proliferation in R6/1 Huntington's mice.

In order to ascertain whether disturbances of neurogenesis occur in chronic neurodegenerative disorders, we assessed hippocampal cell proliferation in the R6/1 transgenic mouse model of Huntington's disease (HD). Using BrdU labelling for dividing cells at two different time points (5 and 20 weeks) in transgenic and wild type control mice, we have shown that cell proliferation in the hippocampus was similar in younger asymptomatic R6/1 mice and wild type controls, but that older R6/1 mice had significantly fewer BrdU cells than controls. Such a decrease in cell proliferation may be relevant to some of the deficits seen in these mice, although further work is needed to prove this.

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PubMed2004

Environmental enrichment rescues protein deficits in a mouse model of Huntington's disease, indicating a possible disease mechanism.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Transgenic mice expressing a human huntingtin transgene containing an expanded CAG repeat (R6/1 model) develop a neurodegenerative disorder closely resembling human HD. Previous work demonstrated that environmental enrichment delays the onset of motor symptoms in this mouse model. We confirmed that at 5 months of age, enrichment ameliorates motor symptoms (assessed using the rotarod test) and prevents loss of body weight induced by the HD transgene. We further examined molecular consequences of enrichment by determining changes in protein levels in the neostriatum, hippocampus, and anterior cortex using quantitative Western blot analysis. Non-enriched HD mice have severe reductions in BDNF in the hippocampus and striatum at 5 months, which are entirely rescued by enrichment. BDNF levels are unaltered by HD in the anterior cortex, suggesting that enrichment might prevent HD-induced impairment of anterograde transport of this neurotrophin to the striatum. NGF is unaffected by HD. Non-enriched HD mice also exhibit deficits in dopamine and cAMP-regulated phosphoprotein (32 kDa) in striatum and anterior cortex. Environmental enrichment rescues the cortical but not the striatal deficit at 5 months. These results suggest that environmental enrichment benefits animals at early stages of the disease by rescuing protein deficits, possibly through rescuing transcription or protein transport problems.

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PubMed2004

Genetic and environmental factors in the pathogenesis of Huntington's disease.

Huntington's disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntington's disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntington's disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntington's disease.

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PubMed2002

Environmental enrichment slows disease progression in R6/2 Huntington's disease mice.

Huntington's disease is a genetic disorder that causes motor dysfunction, personality changes, dementia, and premature death. There is currently no effective therapy. Several transgenic models of Huntington's disease are available, the most widely used of which is the R6/2 mouse, because of its rapid disease progression. Environmental enrichment alters gene expression in the normal mouse brain, and modulates the course of several neurological disorders. Environmentally enriched mice may actually mimic human disease more accurately. We found that even limited environmental enrichment slows decline in RotaRod performance in R6/2 mice, despite rapid disease progression, whereas in normal littermates, maximal enrichment was required to induce a marked improvement in behavioral tests. Enrichment also delayed the loss of peristriatal cerebral volume in R6/2 brains. These results could provide the basis for a rational approach to ameliorate the effects of Huntington's disease.

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