Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer’s Disease: A 5-Year Longitudinal Study

Xie, Bing; Xu, Yao; Liu, Zanchao; Liu, Wenxuan; Jiang, Lei; Zhang, Rui; Cui, Dongsheng; Zhang, Qingfu; Xu, Shunjiang

doi:10.3233/jad-160954

Cited by 47 publications

(32 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The study of diagnosis and treatment of senile dementia in Hebei Province; URL: http://www.chictr.org.cn/showproj.aspx?proj=8194; Registration number: ChiCTR‐RRC‐11001345. We recruited 71 patients with aMCI and 69 normal controls from our previous cross‐sectional cohort study of aMCI in Hebei province (Xie, Liu, Jiang, Liu, et al, ; Xie, Liu, Liu, Jiang, et al, ; Xie, Xu, Liu, Liu, et al, ). All subjects were aged 60 years and older, and aMCI and controls were matched for age and gender.…”

Section: Methodsmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

Self Cite

View full text Add to dashboard Cite

Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.

show abstract

Section: Methodsmentioning

confidence: 99%

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Shi

Zhang

Zhou³

et al. 2020

Aging Cell

Self Cite

View full text Add to dashboard Cite

show abstract

“…For the initial analysis, both HD and PM cases were combined to increase sample size and statistical power. We focused on 12 CpG sites in promoter IV of the BDNF gene (Figure 3) as this region has been previously reported as differentially methylated in Alzheimer's disease and other neurological conditions (Rao et al, 2012;Ikegame et al, 2013;Januar et al, 2015;Kang et al, 2015;Xie et al, 2017). The mean methylation levels for each CpG tested is shown in Figure 4).…”

Section: Dna Methylation Alterations At Bdnf Promoter IVmentioning

confidence: 99%

“…With regards to markers of BDNF gene activity, analyses have focused on DNA methylation of the BDNF promoter in various neurological disorders. Specifically, studies have demonstrated changes in DNA methylation at the BDNF promoter in blood samples from patients with Alzheimer's disease (AD) (Rao et al, 2012;Xie et al, 2017), major depression (Januar et al, 2015;Kang et al, 2015) and schizophrenia (Ikegame et al, 2013). Such studies have suggested that BDNF promoter methylation might be a useful peripheral biomarker of disease symptoms observed in these disorders.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington’s Disease Patients

Gutierrez

Corey–Bloom

Thomas

et al. 2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Huntington's disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brainderived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are

show abstract

“…To check the effect of the p.Arg190His and p.Arg190Cys mutations on AT‐Hook binding at the promoter region of a target gene, we performed EMSA assays with unmethylated 148 bp double stranded DNA sequence from the BDNF promoter IV (NCBI accession KX964617), as described above and elsewhere (Xie et al., ). All experiments were conducted with 120 ng of PCR‐amplified gel‐purified product with protein concentrations 25, 50, 75, and 100 μM (Figure A–D).…”

Section: Resultsmentioning

confidence: 99%

“…Methods). 120 nM of a 65 bp double stranded probe with a single AT‐rich motif (see below), and 120 ng of 148 bp double stranded sequence BDNF promoter IV (NCBI accession KX964617) (Xie et al., ) were used in the EMSA reactions. After annealing, the samples were run on PAGE, and gels were post‐stained with Invitrogen™ SYBR™ Safe DNA Gel Stain and imaged under BioRad's gel documentation system to detect DNA.…”

Section: Methodsmentioning

confidence: 99%

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

et al. 2018

View full text Add to dashboard Cite

Mutations in the methyl-CpG-binding protein-2 gene (MECP2) are commonly associated with Rett syndrome. However, it has long been appreciated that there exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. The most frequent Rett missense mutations are located in either the methyl-CpG-binding domain (MBD) or transcription repression domain (TRD). Clinical roles for mutations in other domains such as the intervening domain (ID) or AT-Hook domains have yet to be determined. Here, we report functional analysis of MECP2 missense mutations, located in AT-Hook1 within the ID, in a large Pakistani family with childhood onset cognitive decline and schizophrenia (SCZ), de novo in a girl with atypical Rett syndrome, and de novo in a woman with SCZ. We show that both p.Arg190His and p.Arg190Cys affect the ability of MeCP2 to bind to AT-rich DNA, also the brain-derived neurotrophic factor (BDNF) promoter, with the more drastic effects seen for p.Arg190Cys. Both mutations also affect nuclear chromatin clustering in vitro. These data support a possible molecular link between MECP2 AT-Hook1 mutations and psychosis. Given the ongoing large-scale whole exome and whole genome sequencing projects for psychiatric disorders, our findings suggest that rare missense variants in MECP2 be carefully evaluated for molecular consequences.

show abstract

Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer’s Disease: A 5-Year Longitudinal Study

Cited by 47 publications

References 41 publications

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington’s Disease Patients

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

Contact Info

Product

Resources

About