Altered High Density Lipoprotein Composition in Behavioral Variant Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a common cause of early onset dementia with behavioral variant FTD (bvFTD) being the most common form. bvFTD is characterized clinically by behavioral and personality changes, eating abnormalities, and pathologically, by systemic lipid dysregulation that impacts on survival. As lipoprotein metabolism is at the core of lipid dysregulation, here, we analyzed the composition, both proteins and lipids, of the two major lipoprotein classes in blood - high density lipoproteins (HDLs) and low density lipoproteins (LDLs). Fasted plasmas from bvFTD and Alzheimer's disease (AD) patients and controls were fractionated using fast protein liquid chromatography (FPLC) and samples analyzed by lipid assays, ELISA and western blotting. We found that apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) levels in HDLs were decreased in bvFTD compared to controls, whereas apolipoprotein B (apoB) levels in LDLs were unaltered. We also found that cholesterol and triglyceride levels in FPLC fractions were altered in bvFTD compared to controls. The apoB:apoA-I ratio and the standard lipid ratios were significantly increased in bvFTD compared to AD and controls. Furthermore, we found that plasma apolipoprotein C-I and paraoxonase 1 levels were significantly altered in bvFTD and AD, respectively, compared controls. This study represents the first apolipoprotein analysis of bvFTD, and our results suggest altered HDL function and elevated cardiovascular disease risk in bvFTD.

Keywords: Alzheimer’s disease; HDL; LDL; apolipoprotein; biomarker; cardiovascular disease risk; frontotemporal dementia; lipid.

FIGURE 1

Fast protein liquid chromatography (FPLC) profiles of behavioral variant frontotemporal dementia (bvFTD), Alzheimer’s disease (AD), and control plasmas. (A) A typical FPLC chromatogram shows peaks at ∼75, 100 and 115 min that correspond to very low density lipoproteins/low density lipoproteins (VLDLs/LDLs), high density lipoproteins (HDLs), and human serum albumin (HSA), respectively. (B) FPLC protein profiles. (C) FPLC cholesterol profiles. (D) FPLC triglyceride profiles.

FIGURE 2

Apolipoprotein levels in lipoproteins in bvFTD, AD, and controls. (A–C) Apolipoprotein assay standard curves with R² value. (D–F) Confirmation that apoA-I and apoA-II are present only in HDLs and apoB is present only in VLDLs/LDLs. (G–I) Concentrations of apolipoproteins in bvFTD, AD, and controls. Bars represent mean and SE, ^∗p < 0.05.

FIGURE 3

Lipid and protein levels in lipoproteins in bvFTD, AD, and controls. (A–D) Lipid and protein assay standard plots with R² value. (E–H) Concentrations of lipids and protein in HDLs and VLDLs/LDLs in bvFTD, AD, and controls. (I) A comparison of total triglyceride measurements using FPLC, enzyme-based assay, and mass spectrometry. (J) The VLDL-triglyceride:HDL-cholesterol ratio is significantly increased in bvFTD compared to AD and controls. Data represent mean and SE as error bars, ^∗p < 0.05.

FIGURE 4

Increased risk for cardiovascular disease (CVD) in bvFTD. (A) The apoB:apoA-I ratio was significantly increased in bvFTD; a ratio value greater than 1.0 (red line) is regarded as increased CVD risk. (B) The apoB:apoA-II ratio was significantly increased in bvFTD. (C) The apoA-I:apoA-II ratio was unchanged in bvFTD and AD. (D) The triglyceride:HDL-cholesterol ratio was significantly increased in bvFTD; a ratio value greater than 0.87 (red line) is regarded as increased CVD risk. (E) The total cholesterol:HDL-cholesterol ratio was significantly increased in bvFTD; a ratio value greater than 5.0 (red line) is regarded as increased CVD risk. Bars represent mean and SE, ^∗p < 0.05. (F) ApoA-I levels correlated positively with HDL-cholesterol levels.

FIGURE 5

ApoA-I levels in whole plasma in bvFTD, AD, and controls. (A) Western blotting of plasma apoA-I; transferrin was used as a loading control. (B) Relative optical density of protein bands. Data represent mean (n = 6, 5, 6, respectively) and SE as error bars, ^∗p < 0.05. (C) HDL fraction apoA-I levels correlated positively with whole plasma apoA-I levels. (D) No significant difference between fasted and non-fasted apoA-I levels in whole plasma.

FIGURE 6

ApoC-I, PON1, and SERPINA1 levels in whole plasma in bvFTD, AD, and controls. (A) Western blotting of plasma apoC-I; transferrin was used as a loading control. (B) Relative optical density of protein bands; data represent mean and SE as error bars, ^∗p < 0.05. (C) PON1 levels were significantly increased in AD compared to both bvFTD and controls as measured by ELISA; bars represent mean and SE, ^∗p < 0.05. (D) SERPINA1 levels were unaltered in both bvFTD and AD compared to controls as measured by ELISA.