Dataset Information

Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.

ABSTRACT: The medium subunit of neurofilament (NF-M) is extensively modified by phosphate and O-linked beta-N-acetylglucosamine (O-GlcNAc). Phosphorylation of NF-M plays a critical role in regulating its translocation, filament formation, and function. However, the regulation of NF-M phosphorylation and the role of NF-M O-GlcNAcylation (a modification by which GlcNAc is attached to the serine/threonine residues of a protein via an O-linked glycosidic bond) are largely unknown. Here, we demonstrate that O-GlcNAcylation and phosphorylation of NF-M regulate each other reciprocally in cultured neuroblastoma cells and in metabolically active rat brain slices. In animal models of fasting rats, which mimicked the decreased glucose uptake/metabolism observed in brains of individuals with Alzheimer disease (AD), we found a decrease in O-GlcNAcylation and increase in phosphorylation of NF-M. We also observed decreased O-GlcNAcylation and an increased phosphorylation of NF-M in AD brain. These results suggest that O-GlcNAcylation and phosphorylation of NF-M are regulated reciprocally and that the hyperphosphorylation and accumulation of NF-M in AD brain might be caused by impaired brain glucose uptake/metabolism via down-regulation of NF-M O-GlcNAcylation.

SUBMITTER: Deng Y

PROVIDER: S-EPMC2262915 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.

Deng Yanqiu Y Li Bin B Liu Fei F Iqbal Khalid K Grundke-Iqbal Inge I Brandt Roland R Gong Cheng-Xin CX

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20070808 1

The medium subunit of neurofilament (NF-M) is extensively modified by phosphate and O-linked beta-N-acetylglucosamine (O-GlcNAc). Phosphorylation of NF-M plays a critical role in regulating its translocation, filament formation, and function. However, the regulation of NF-M phosphorylation and the role of NF-M O-GlcNAcylation (a modification by which GlcNAc is attached to the serine/threonine residues of a protein via an O-linked glycosidic bond) are largely unknown. Here, we demonstrate that O- ...[more]

PMID: 17687114

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Project description:ImportancePlasma neurofilament light (NfL) has been suggested as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD), but studies are lacking.ObjectiveTo examine whether longitudinal plasma NfL levels are associated with other hallmarks of AD.Design, setting, and participantsThis North American cohort study used data from 1583 individuals in the multicenter Alzheimer's Disease Neuroimaging Initiative study from September 7, 2005, through June 16, 2016. Patients were eligible for inclusion if they had NfL measurements. Annual plasma NfL samples were collected for up to 11 years and were analyzed in 2018.ExposuresClinical diagnosis, Aβ and tau cerebrospinal fluid (CSF) biomarkers, imaging measures (magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography), and tests on cognitive scores.Main outcomes and measuresThe primary outcome was the association between baseline exposures (diagnosis, CSF biomarkers, imaging measures, and cognition) and longitudinal plasma NfL levels, analyzed by an ultrasensitive assay. The secondary outcomes were the associations between a multimodal classification scheme with Aβ, tau, and neurodegeneration (ie, the ATN system) and plasma NfL levels and between longitudinal changes in plasma NfL levels and changes in the other measures.ResultsOf the included 1583 participants, 716 (45.2%) were women, and the mean (SD) age was 72.9 (7.1) years; 401 had no cognitive impairment, 855 had mild cognitive impairment, and 327 had AD dementia. The NfL level was increased at baseline in patients with mild cognitive impairment and AD dementia (mean levels: cognitive unimpairment, 32.1 ng/L; mild cognitive impairment, 37.9 ng/L; and AD dementia, 45.9 ng/L; P < .001) and increased in all diagnostic groups, with the greatest increase in patients with AD dementia. A longitudinal increase in NfL level correlated with baseline CSF biomarkers (low Aβ42 [P = .001], high total tau [P = .02], and high phosphorylated tau levels [P = .02]), magnetic resonance imaging measures (small hippocampal volumes [P < .001], thin regional cortices [P = .009], and large ventricular volumes [P = .002]), low fluorodeoxyglucose-positron emission tomography uptake (P = .01), and poor cognitive performance (P < .001) for a global cognitive score. With use of the ATN system, increased baseline NfL levels were seen in A-T+N+ (P < .001), A+T-N+ (P < .001), and A+T+N+ (P < .001), and increased rates of NfL levels were seen in A-T+N- (P = .009), A-T+N+ (P = .02), A+T-N+ (P = .04), and A+T+N+ (P = .002). Faster increase in NfL levels correlated with faster increase in CSF biomarkers of neuronal injury, faster rates of atrophy and hypometabolism, and faster worsening in global cognition (all P < .05 in patients with mild cognitive impairment; associations differed slightly in cognitively unimpaired controls and patients with AD dementia).Conclusions and relevanceThe findings suggest that plasma NfL can be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and may be useful to monitor effects in trials of disease-modifying drugs.

Project description:ImportanceExisting cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias.ObjectiveTo test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration.Design, setting, and participantsIn this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016.Main outcomes and measuresAssociations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism.ResultsAmong 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally).Conclusions and relevancePlasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

Dataset Information

Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.

Publications

Regulation between O-GlcNAcylation and phosphorylation of neurofilament-M and their dysregulation in Alzheimer disease.

Similar Datasets

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