Synapse loss in dementias

Clare, Ryan; King, Victoria G.; Wirenfeldt, Martin; Vinters, Harry V.

doi:10.1002/jnr.22392

Cited by 144 publications

(131 citation statements)

References 58 publications

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“…Expression of the IBMPFD mutants reduces the number of dendritic spines in cultured hippocampal neurons by 10%-18%. Since synapse loss has been suggested in various neurological disorders associated with dementia (61)(62)(63)(64)(65)(66)(67), the ability of VCP in the regulation of spinogenesis may be relevant to clinical features of dementia in patients. VCP does not represent the only example where a gene responsible for FTD is involved in neuronal morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Wang¹,

Shih²,

Chen³

et al. 2011

J. Clin. Invest.

104

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Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1 +/-mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.

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Section: Discussionmentioning

confidence: 99%

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Wang¹,

Shih²,

Chen³

et al. 2011

J. Clin. Invest.

104

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“…Reactive oxidative stress and inflammatory cytokines have important roles in brain impairment and dementia progression (8). In addition, experimental evidence has indicated that synapse loss occurs in AD and VaD patients and studies revealed a strong correlation between synapse reduction and the severity of dementia (9). Although an increasing number of mechanistic pathological studies focused on VaD and hypoperfusion, no effective pharmacological intervention has been approved by the Food and Drug Administration (Silver Spring, MD, USA) and used clinically.…”

Section: Introductionmentioning

confidence: 99%

Bushen Huoxue decoction improves cognitive decline in rats with cerebral hypoperfusion

et al. 2014

Molecular Medicine Reports

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Abstract. Cerebral hypoperfusion is a common feature of vascular dementia and has recently been recognized to contribute to the progression of cognitive decline. The present study aimed to investigate the effects of Bushen Huoxue decoction (BHD), a two-herb Chinese Medicine, on cognitive impairment in a rat model of cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (2VO). The results demonstrated that BHD significantly attenuated learning and spatial memory deficits in the Morris water maze test in a dose-dependent manner. Transmission electron microscopy observation revealed that the reduction of synapse density in hippocampal CA1 and cortex parietal isolated from rats with 2VO was partially restored by BHD treatment. In addition, the expression levels of a number of antioxidants, including superoxide dismutase, catalase (CAT), glutathine and glutathione peroxidase-1 (GPx-1) increased, whereas malondialdehyde decreased in the hippocampi of rats with 2VO following BHD treatment. Polymerase chain reaction and western blot analysis further confirmed that the GPx-1 and CAT expression increased in the BHD treatment group. In conclusion the results suggested that BHD has therapeutic potential to treat vascular dementia, which may be associated with synapse density and anti-oxidant activities in the hippocampus.

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“…The proposed therapeutic mechanism of Souvenaid™ on synaptic function makes it a clinically interesting drug in bv-FTD, that is, a neurodegenerative condition linked with different neuropathological substrata, all presenting synaptic dysfunction as a final common pathway [1,6,7,8]. Here, we thus decided to assess the effects of Souvenaid™ on these key symtomatological domains of bv-FTD, namely executive functions, behavioral symptomatology and social cognition [9].…”

Section: Introductionmentioning

confidence: 99%

“…Synaptic dysfunction and loss is one of the final common pathways of neurodegeneration [1], thus potentially representing a relevant therapeutic target in different neurological conditions. Despite the possible clinical usefulness of targeting synaptic dysfunction, the currently available pharmacological options to reach this aim in the clinical setting are limited.…”

Section: Introductionmentioning

confidence: 99%

Souvenaid Reduces Behavioral Deficits and Improves Social Cognition Skills in Frontotemporal Dementia: A Proof-of-Concept Study

et al. 2015

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Background: Souvenaid™ is a nutraceutical compound thought to positively enhance synaptic function. In line with this mechanism of action, Souvenaid™ has been shown to improve cognitive function in subjects with mild Alzheimer's disease in randomized clinical trials. To date, however, the potential of Souvenaid™ to improve cognitive functioning in subjects with other neurodegenerative conditions also characterized by synaptic loss has not been explored. Objective: To evaluate the impact of Souvenaid™ on executive functions, social cognition and behavioral disturbances in subjects with the behavioral variant of frontotemporal dementia (bv-FTD). Methods: Twenty-six subjects with bv-FTD were enrolled in the study and randomized to Souvenaid™ (125 ml/day) or placebo groups. After 12 weeks, subjects were switched between the two groups. All subjects, blinded to treatment, underwent clinical and cognitive evaluations at enrollment, after 12 weeks and after 24 weeks. Results: Treatment with Souvenaid™ was associated with a significant reduction of behavioral symptoms and an increase in Theory of Mind skills compared to placebo, which both returned to baseline when Souvenaid™ was discontinued. Souvenaid™ did not have an effect on executive functions. Conclusions: Our results provide evidence of the potential of Souvenaid™ therapy for the treatment of behavioral disturbances and social cognition skills in FTD.

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Synapse loss in dementias

Cited by 144 publications

References 58 publications

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Bushen Huoxue decoction improves cognitive decline in rats with cerebral hypoperfusion

Souvenaid Reduces Behavioral Deficits and Improves Social Cognition Skills in Frontotemporal Dementia: A Proof-of-Concept Study

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