Correlates and Predictors of Cerebrospinal Fluid Cholesterol Efflux Capacity from Neural Cells, a Family of Biomarkers for Cholesterol Epidemiology in Alzheimer’s Disease

Cipollari, Eleonora; Szapary, Hannah J.; Picataggi, Antonino; Billheimer, Jeffrey T.; Lyssenko, Catherine A; Ying, Gui‐Shuang; Shaw, Leslie M.; Kling, Mitchel A.; Kaddurah‐Daouk, Rima; Rader, Daniel J.; Praticò, Domenico; Lyssenko, Nicholas N.

doi:10.3233/jad-191246

Cited by 7 publications

(13 citation statements)

References 58 publications

(84 reference statements)

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“…Likewise, cholesterol efflux to the CSF from ApoE3 carriers was significantly increased compared to that from ApoE4 carriers in ABCA1-induced BHK cells [ 110 ]. Despite the importance of these findings, only one work has performed similar studies in cells that are functionally and morphologically relevant in the brain and, thus, for AD pathology [ 151 ], representing a proof of concept for CSF cholesterol efflux quantification in human neurological cells. Efflux measurement in neurons, microglia, and astrocytes allowed researchers to conclude that CSF cholesterol efflux levels are positively correlated with total cholesterol, ApoA-I, ApoE, and ApoJ concentrations.…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

“…Efflux measurement in neurons, microglia, and astrocytes allowed researchers to conclude that CSF cholesterol efflux levels are positively correlated with total cholesterol, ApoA-I, ApoE, and ApoJ concentrations. However, demographic and clinical data were unknown because the CSF samples were taken from anonymous patients, making it impossible to compare efflux among healthy controls and patients with AD [ 151 ].…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

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HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

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Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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“…Two isoforms are encoded by the CLU gene: a truncated nuclear form and a conventional omnipresent secretory heterodimeric disulfide-linked glycoprotein 14 . CLU is highly expressed in patients with diabetes 15 , atherosclerosis 16 , and tumorigenesis 17 . The role of CLU in LFH has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Lian

Liu

et al. 2022

Exp Mol Med

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Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal canal stenosis (LSCS). The pathomechanisms for LFH have not been fully elucidated. Isobaric tags for relative and absolute quantitation (iTRAQ) technology, proteomics assessments of human ligamentum flavum (LF), and successive assays were performed to explore the effect of clusterin (CLU) upregulation on LFH pathogenesis. LFH samples exhibited higher cell positive rates of the CLU, TGF-β1, α-SMA, ALK5 and p-SMAD3 proteins than non-LFH samples. Mechanical stress and TGF-β1 initiated CLU expression in LF cells. Notably, CLU inhibited the expression of mechanical stress-stimulated and TGF-β1-stimulated COL1A2 and α-SMA. Mechanistic studies showed that CLU inhibited mechanical stress-stimulated and TGF-β1-induced SMAD3 activities through suppression of the phosphorylation of SMAD3 and by inhibiting its nuclear translocation by competitively binding to ALK5. PRKD3 stabilized CLU protein by inhibiting lysosomal distribution and degradation of CLU. CLU attenuated mechanical stress-induced LFH in vivo. In summary, the findings showed that CLU attenuates mechanical stress-induced LFH by modulating the TGF-β1 pathways in vitro and in vivo. These findings imply that CLU is induced by mechanical stress and TGF-β1 and inhibits LF fibrotic responses via negative feedback regulation of the TGF-β1 pathway. These findings indicate that CLU is a potential treatment target for LFH.

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“…In serum, ApoA1-containing lipoproteins are the main acceptors and are much higher in concentration than ApoE or ApoJ. Because cellular cholesterol is thought to play a role in AD, we adapted the CEC assay to use neuronal cells as source and CSF as acceptor [ 17 ]. Unlike serum, the concentration of ApoA1 is similar to that of ApoE and ApoJ in CSF such that all three may play a major role in efflux.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike serum, the concentration of ApoA1 is similar to that of ApoE and ApoJ in CSF such that all three may play a major role in efflux. Initial studies have shown that among the cells and conditions used, neuronal cells are a less important source cell than microglia, showing less efflux to ApoA1 and HDL [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer’s disease

Billheimer

Lyssenko

et al. 2022

Alz Res Therapy

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Background Alzheimer’s disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC. Methods We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [3H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 μl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [3H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF. Results We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aβ. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.

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Correlates and Predictors of Cerebrospinal Fluid Cholesterol Efflux Capacity from Neural Cells, a Family of Biomarkers for Cholesterol Epidemiology in Alzheimer’s Disease

Abstract: Background: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer's disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD.

Cited by 7 publications

References 58 publications

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer’s disease

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