Distinct patterns of apolipoprotein C-I, C-II, and C-III isoforms are associated with markers of Alzheimer’s disease

Abstract

Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1 ) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2 ) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APO E Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.

Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression

“…Apoptosis can directly damage the endothelium, making it prone to atherosclerosis injury. Concomitant aberration in monocyte differentiation can propel atherosclerosis by activating one of pro-atherosclerotic subpopulations of monocytes: atypical monocyte 2 (M2) or foamy cells [ 33 , 39 , 41 , 54 , 56 , 57 , 58 , 66 , 153 , 182 , 183 , 184 ]. M2 represents an atypical, activated monocyte that produces a significant amount of monocyte-colony stimulating factor (M-CSF) and free radicals, while not being able to mount an effective response to invading pathogens.…”

“…Detergent-like features enabling hydrophobic material to enter into the micelle of lipoproteins are provided by apolipoproteins (Apo). Apo is also critical in regulating the turnover of lipoproteins through different cells and organs [52,[64][65][66][67][68]. Several apolipoprotein types exist with diverse physiological functions and corresponding roles in different diseases (Table 1).…”

“…Appetite [78], antioxidants metabolism, lipid transport. Thermogenesis [79,80] Schizophrenia [81] A5(A-V) Regulation of TG levels Metabolic syndrome [82], cardiovascular disease progression [83] B48 Chylomicrons, VLDL-C Staphylococcal infection defence [49,51], weight loss, carbohydrate metabolism [84], Lipid transport [59] Infection resistance [49,51], insulin resistance [84], venous thrombosis [85] B100 Chylomicrons Staphylococcal infection defence [51], Lipid transport [59] Cardiovascular progression [59], insulin resistance, infection resistance [49,51], venous thrombosis [85] C-I HDL, VLDL-C, chylomicrons Lipid metabolism [86] Alzheimer's disease [66,87], cancer promoting [88], venous thrombosis [85], pancreatitis, hepatosplenomegaly C-II VLDL-C, chylomicrons Lipid metabolism [67,86] Alzheimer's disease [66,87] C-III VLDL-C, chylomicrons, remnant cholesterol, HDL Lipid metabolism [68] Alzheimer's disease [66], coronary artery disease [68,89] C-IV Liver Lipid metabolism [86] Alzheimer's disease [90], stroke [91] D Brain, testes, HDL Lipoprotein metabolism [64], hormone binding [64], neuronal regeneration [69,92], inflammation…”

Understanding the Exchange of Systemic HDL Particles Into the Brain and Vascular Cells Has Diagnostic and Therapeutic Implications for Neurodegenerative Diseases

“…This suggests that the lipidation of delipidated and/or lipidpoor apos within the CP occurs in lieu of HDL transport across the BCSFB from the periphery. This hypothesis is supported by associations among plasma and CSF apos' concentrations (Koch et al, 2017;Hu et al, 2020). The process in which lipid-poor HDL-P or lipid-free apos (made of apoA-I, apoA-II, apoA-IV, apoCs, and apoE) originating in the periphery become lipidated by CNS-expressed transporters following transport across the BCSFB likely affects brain Aβ accumulation and is discussed in section "Effect of HDL Proteins on CNS Aβ Accumulation and Related Pathology.…”

“…There are, however, limitations to apoE-HDL-mediated uptake. For example, CSF-derived apoE (Holzer et al, 2016;Kuklenyik et al, 2018) 1:150 (Memisogullari and Bakan, 2004;Mizuno et al, 2005) ApoA-I Liver, intestine Limited BBB permeability Yes (Stukas et al, 2014a) Potentially involved in SR-BI mediated endocytosis of HDL at BBB [50] Small and large HDL (Holzer et al, 2016;Kuklenyik et al, 2018) 1:700 (Koch et al, 2017) ApoA-II Liver, intestine Unknown Yes (Montine et al, 1998) -Small and large HDL (Holzer et al, 2016;Kuklenyik et al, 2018) 1:636* ApoC-I Liver, neurons, astrocytes Some evidence (Cudaback et al, 2012) Yes Inhibits LRP-1, LDLR Small and large HDL (Kuklenyik et al, 2018) 1:1,000 (Hu et al, 2020) ApoC-II Liver -Yes Inhibits LRP-1, LDLR Small and large HDL (Kuklenyik et al, 2018) 1:3,000 (Hu et al, 2020) ApoC-III Liver Some evidence (Zhou et al, 2019) Yes (Koch et al, 2017) Inhibits LDLR Small and large HDL (Kuklenyik et al, 2018), Gordts and Esko, 2018;Foley et al, 2013) 1:2,000 (Hu et al, 2020)…”