The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid

Harrington, Michael G.; Fonteh, Alfred N.; Oborina, Elena; Liao, Patricia; Cowan, Robert P.; McComb, Gordon; Chavez, Jesus; Rush, A. John; Biringer, Roger G.; Hühmer, Andreas

doi:10.1186/1743-8454-6-10

Cited by 65 publications

(71 citation statements)

References 57 publications

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“…The supernatant and nanoparticle fractions reported in this study are both from this final fractionation step. Electron microscopy of nanoparticles with negative staining was performed using a Morgagni 268D transmission electron microscope (FEI), as described previously 19. Examples of nanoparticles revealed by transmission electron microscopy from a control participant are shown in Figure S2A, which demonstrates their high abundance, heterogeneity, and prominent membranes.…”

Section: Methodsmentioning

confidence: 99%

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Yassine

Feng

Chiang

et al. 2016

JAHA

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BackgroundAnimal and human studies indicate that ABCA1‐mediated cholesterol transport is important in Alzheimer's disease (AD). We hypothesized that the efficiency of cerebrospinal fluid (CSF) to facilitate ABCA1‐mediated cholesterol efflux would be reduced in participants with mild cognitive impairment (MCI) or AD compared with cognitively healthy participants.Methods and ResultsCSF was collected from a cross‐sectional study of cognitively healthy participants (n=47) and participants with MCI (n=35) or probable AD (n=26).The capacity of CSF to mediate cholesterol transport was assessed using a BHK cell line that can be induced to express the ABCA1 transporter. ABCA1‐mediated cholesterol efflux capacity was 30% less in participants with MCI or AD compared with cognitively healthy participants (P<0.001 for both). Cholesterol efflux capacity correlated with CSF cholesterol content (r=0.37, P<0.001). CSF phosphatidylcholine decreased in participants with MCI and AD compared with cognitively healthy participants (9% less in MCI and 27% less in AD compared with cognitively healthy participants, P=0.01) and correlated with CSF efflux capacity (r=0.3, P=0.001). CSF sphingomyelin also correlated with the efflux capacity (r=0.24, P=0.02). Concentrations of CSF apoA‐I and apoE did not significantly correlate with measures of efflux capacity.ConclusionsIn people with MCI and AD, the capacity of CSF to facilitate ABCA1‐mediated cholesterol efflux is impaired. This lesser cholesterol efflux in MCI supports a pathophysiological role for ABCA1‐mediated cholesterol transport in early neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Yassine

Feng

Chiang

et al. 2016

JAHA

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“…However, our study demonstrates that these proteins are detected at the expected molecular weight, indicating that there is no fragmentation, or at least that they are intact in part. Harrington et al (2009) identified the presence of CSF membranous nanostructures, thought to play a physiologically active role, and not merely the result of blebbing, apocrine secretion, or apoptosis events, or cellular debris. These structures can provide an appropriate environment for transmembrane proteins which are hydrophobic in nature.…”

Section: Discussionmentioning

confidence: 99%

Analysis of synaptic proteins in the cerebrospinal fluid as a new tool in the study of inborn errors of neurotransmission

Duarte

Ortez

Perez

et al. 2011

J of Inher Metab Disea

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In a few rare diseases, specialised studies in cerebrospinal fluid (CSF) are required to identify the underlying metabolic disorder. We aimed to explore the possibility of detecting key synaptic proteins in the CSF, in particular dopaminergic and gabaergic, as new procedures that could be useful for both pathophysiological and diagnostic purposes in investigation of inherited disorders of neurotransmission. Dopamine receptor type 2 (D2R), dopamine transporter (DAT) and vesicular monoamine transporter type 2 (VMAT2) were analysed in CSF samples from 30 healthy controls (11 days to 17 years) by western blot analysis. Because VMAT2 was the only protein with intracellular localisation, and in order to compare results, GABA vesicular transporter, which is another intracellular protein, was also studied. Spearman's correlation and Student's t tests were applied to compare optical density signals between different proteins. All these synaptic proteins could be easily detected and quantified in the CSF. DAT, D2R and GABA VT expression decrease with age, particularly in the first months of life, reflecting the expected intense synaptic activity and neuronal circuitry formation. A statistically significant relationship was found between D2R and DAT expression, reinforcing the previous evidence of DAT regulation by D2R. To our knowledge, there are no previous studies on human CSF reporting a reliable analysis of these proteins. These kinds of studies could help elucidate new causes of disturbed dopaminergic and gabaergic transmission as well as understanding different responses to L-dopa in inherited disorders affecting dopamine metabolism. Moreover, this approach to synaptic activity in vivo can be extended to different groups of proteins and diseases.

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“…How closely CSF lipids mirror those in the brain remains to be determined, but we recently described nanometer-sized membrane particles (NPs) that have rich lipid content, functionally active enzymes, and neurotransmitters distinct from the surrounding supernatant fl uid (SF) ( 24 ). Though the mechanism for the formation of these CSF fractions remains to be determined, NPs can be considered to represent some of the brain tissue components, and the SF fraction represents extracellular fl uids.…”

Section: Csf Fractionation and Gp Extractionmentioning

confidence: 99%

“…CSF membranes were prepared as described ( 24 ). Briefl y, 4 ml of CSF was centrifuged at 17,000 g , and the resulting supernatant fl uid was centrifuged again at 200,000 g .…”

Section: Csf Fractionation and Gp Extractionmentioning

confidence: 99%

Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease

Fonteh

Chiang

Cipolla

et al. 2013

Journal of Lipid Research

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The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid

Cited by 65 publications

References 57 publications

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Analysis of synaptic proteins in the cerebrospinal fluid as a new tool in the study of inborn errors of neurotransmission

Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease

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