Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

Kemppainen, Susanna; Lindholm, Päivi; Galli, Emilia; Lahtinen, Hanna-Maija; Koivisto, Hennariikka; Hämäläinen, Elina; Saarma, Märt; Tanila, Heikki

doi:10.1016/j.bbr.2015.05.002

Cited by 51 publications

(27 citation statements)

References 31 publications

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“…CDNF has strong neuroprotective and restorative effects in animal models of PD [ 22 ], and protects dopaminergic neurons in the 6-hydroxydopamine rat model [ 14 , 23 ]. However, the genotype and allele frequencies of the CDNF SNPs rs1901650 and rs11259365 did not differ between PD patients and controls; only the C allele of CDNF rs7094179, an intronic SNP, has been linked to PD susceptibility [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Association between cerebral dopamine neurotrophic factor (CDNF) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Yang

et al. 2018

Behav Brain Funct

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BackgroundSchizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ.MethodsTo address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls.ResultsWe found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ2 = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at rs2249810 (χ2 = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ2 = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01).ConclusionsThese results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population.

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Section: Discussionmentioning

confidence: 99%

Association between cerebral dopamine neurotrophic factor (CDNF) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Yang

et al. 2018

Behav Brain Funct

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“…Other therapeutic approaches to AD gene therapy are more tangential, including AAV delivery of a FK506-binding protein (FKBP1b) that stabilizes Ca++ release from the endoplasmic reticulum in neurons (Gant et al, 2015) or delivery of growth factors that help neurons survive toxic injury, including delivery of cerebral dopamine neurotrophic factor (CDNF) (Kemppainen et al, 2015), insulin growth factor (Pascual-Lucas et al, 2014), brain-derived neurotrophic factor (BDNF; Nagahara et al, 2013) and nerve growth factor (NGF; Tuszynski et al, 2015) to the brain using different virus vectors. The latter has proceeded to promising clinical trials.…”

Section: Different Modalities For Different Diseasesmentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

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“…Growth factors GDNF, CDNF, MANF, FGF2, brainderived neurotrophic factor (BDNF), epidermal growth factor (EGF) and heparin-binding epidermal growth factor (HB-EGF) were chosen for inclusion in this study based on reports demonstrating these factors to be neuroprotective or neurorestorative for dopaminergic neurons (9,17,20,21,34,36), or that these factors support learning and memory in animal models of AD (40,41,58,65,94). Hippocampal levels of these factors were quantified in ten cases of PD and nine age-matched normal controls.…”

Section: Methodsmentioning

confidence: 99%

“…Studies of growth factors as candidate therapies in animal models of AD suggests these factors can reduce hippocampal pathology and restore memory function. For example, in rodent models hippocampal‐targeted GDNF protects against AD‐associated pathology , while CDNF improves long‐term memory in a transgenic AD mouse model . FGF2 gene therapy reduces hippocampal plaque load, stimulates neurogenesis, and restores spatial learning in a mutant mouse model of AD .…”

Section: Introductionmentioning

confidence: 99%

Levels of glial cell line‐derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson’s disease

et al. 2019

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Growth factors can facilitate hippocampus‐based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson’s disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme‐linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age‐matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line‐derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin‐binding epidermal growth factor, brain‐derived neurotrophic factor and mesencephalic astrocyte‐derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline.

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Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

Cited by 51 publications

References 31 publications

Association between cerebral dopamine neurotrophic factor (CDNF) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Association between cerebral dopamine neurotrophic factor (CDNF) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Viral vectors for therapy of neurologic diseases

Levels of glial cell line‐derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson’s disease

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