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. 2022 Dec 26;14(1):194.
doi: 10.1186/s13195-022-01119-z.

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

Yi-An Ko #  1 , Jeffrey T Billheimer #  1 , Nicholas N Lyssenko  2 , Alexandra Kueider-Paisley  3 , David A Wolk  4 , Steven E Arnold  5 , Yuk Yee Leung  6 , Leslie M Shaw  7 , John Q Trojanowski  1 , Rima F Kaddurah-Daouk  3   8   9 , Mitchel A Kling  10   11 , Daniel J Rader  12
Affiliations

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

Yi-An Ko et al. Alzheimers Res Ther. .

Abstract

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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Conflict of interest statement

R.F.K.-D. is inventor on key patents in the field of metabolomics including applications for Alzheimer’s disease. She holds equity in Metabolon Inc. R.F.K-D. formed Chymia LLC and PsyProtix, a Duke University biotechnology spinout aiming to transform the treatment of mental health disorders.

L.M.S. received research support from NIH/NIA, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (AG024904), and University of Pennsylvania ADCC Biomarker Core (AG010124), Michael J. Fox Foundation for Parkinson’s Research, Roche, and Lilly; provides QC oversight for Roche Elecsys CSF AD biomarker immunoassays for ADNI; and is a consultant for Roche, Lilly, and Novartis.

D.A.W. reports grants from Merck, Biogen, and Eli Lilly/Avid and additional fees from GE Healthcare, Functional Neuromodulation, Eli Lilly, Qynapse, and Neuronix, all outside of this work.

S.E.A. has received fees for serving on advisory boards for Allyx Therapeutics, Inc., Bob’s Last Marathon, Cassava, Cortexyme, Inc., Sage Therapeutics, Inc., vTv Therapeutics, Inc., and for consulting to AbbVie, Inc., Boyle Shaughnessy Law, Cognito Therapeutics, Inc., EIP Pharma, Inc., M3 Biotech, Inc., Orthogonal Neuroscience, Inc., and Risen Pharmaceutical Technology Co, Ltd. He has received sponsored research grant support from the following commercial entities: AbbVie, Inc., Amylyx, Inc., Athira Pharma, Inc., Chromadex, Inc., EIP Pharma, Inc., Janssen Pharmaceuticals, Inc., Novartis AG, Seer Biosciences, Inc., and vTv Therapeutics, Inc. He has received sponsored research grant support from the following non-commercial entities: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Challenger Foundation, John Sperling Foundation, and the National Institutes of Health.

D.J.R. serves on the scientific advisory boards of Alnylam, Novartis, Pfizer, and Verve Therapeutics and is a Founder of Vascular Strategies and Staten Biotechnologies. He has received sponsored research support from Biogen Inc.

Figures

Fig. 1
Fig. 1
Multinomial logistic regression analyses for CSF cholesterol efflux capacity (CEC). The predictions were evaluated for MCI and AD groups against CN. CSF cholesterol efflux capacity was measured in CN (n = 50), MCI (n = 18), and AD (n = 40). The CEC values were normalized to a standard CSF sample that was run on each plate to account for inter-assay variability. We then log normalized the data prior to regression analysis. A Multinomial logistic regression analysis showed N9 CEC has a significant prediction of MCI. B Multinomial logistic regression analysis showed SHSY-5Y CEC has a significant prediction of MCI Detailed statistics are shown in the lower part of the figure. CN, cognitively normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; CEC, cholesterol efflux capacity
Fig. 2
Fig. 2
Multivariate linear regression of CSF CEC and apolipoproteins CSF. CSF cholesterol efflux capacity was measured in CN (n = 50), MCI (n = 18), and AD (n = 40). Association between ApoA1, ApoE, and ApoJ with both CEC in human microglial and neuronal cells (N9 and SH-SY5Y, respectively). Association between ApoA1 significantly associated with N9 microglial and SH-SY5Yneuronal cell CEC (**P < 8.96e−11 and ***P < 3.244e−06, respectively), ApoJ is significantly associated with N9 microglial and SH-SY5Yneuronal cell CEC (**P < 2.22e−05 and *P < 1.22e−02, respectively). ApoE is not associated with either CEC measurement
Fig. 3
Fig. 3
Heat map and hierarchical clustering of CSF CEC with apolipoproteins and biomarkers of AD. CSF CEC is closely associated with ApoA-I and Clusterin. Aβ1-42 is associated with ApoE, and pTau, TTau, and pTau/Aβ1-42 ratio
Fig. 4
Fig. 4
Multinomial logistic regression analyses for CSF apolipoproteins and AD diagnosis. Apolipoproteins were measured in CN (n = 50), MCI (n = 18), and AD (n = 40). A Apo A1 displayed significant prediction of MCI diagnosis. B ApoE is significantly lower in AD (**P < 0.01). C ApoJ (Clusterin) is significantly lower in MCI (**P < 0.01) AD denotes Alzheimer’s disease, CSF cerebrospinal fluid, ApoA1 apolipoprotein A-I, ApoE apolipoprotein E, ApoJ/Clusterin, PL phosphorylated lipid, and Aβ1-42 42 amino acid form of beta amyloid
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