Endothelial-derived plasma exosome proteins in Alzheimer's disease angiopathy

Abstract

Small cerebral vascular disease (SCeVD) demonstrated by white matter hyperintensity (WMH) on MRI contributes to the development of dementia in Alzheimer's disease (AD), but it has not been possible to correlate onset, severity, or protein components of SCeVD with characteristics of WMH in living patients. Plasma endothelial-derived exosomes (EDEs) were enriched by two-step immunoabsorption from four groups of participants with no clinical evidence of cerebrovascular disease: cognitively normal (CN) without WMH (CN without SCeVD, n = 20), CN with SCeVD (n = 22), preclinical AD (pAD) + mild cognitive impairment (MCI) without SCeVD (pAD/MCI without SCeVD, n = 22), and pAD/MCI with SCeVD (n = 16) for ELISA quantification of cargo proteins. Exosome marker CD81-normalized EDE levels of the cerebrovascular-selective biomarkers large neutral amino acid transporter 1 (LAT-1), glucose transporter type 1 (Glut-1), and permeability-glycoprotein (p-GP, ABCB1) were similarly significantly higher in the CN with SCeVD and pAD/MCI with SCeVD groups than their corresponding control groups without SCeVD. CD81-normalized EDE levels of Aβ40 and Aβ42 were significantly higher in the pAD/MCI with SCeVD group but not in the CN with SCeVD group relative to controls without SCeVD. Levels of normal cellular prion protein (PrPc), a receptor for amyloid peptides, and phospho-181T-tau were higher in both CN and pAD/MCI with SCeVD groups than in the corresponding controls. High EDE levels of Aβ40, Aβ42, and phospho-181T-tau in patients with WMH suggesting SCeVD appear at the pre-clinical or MCI stage of AD and therapeutic lowering of neurotoxic peptide levels may delay progression of AD angiopathy.

Keywords: P-tau protein; amyloid; prion cellular protein; small cerebral vascular disease.

FIGURE 1

EDE levels of cerebrovascular-selective cargo proteins in cognitively normal group without SCeVD (CN-no SCeVD), cognitively normal group with SCeVD (CN-SCeVD), pAD/MCI group without SCeVD (pAD/MCI-no SCeVD), and pAD/MCI group with SCeVD (pAD/MCI-SCeVD). Each point represents the value for one participant and the horizontal line in point clusters is the mean level for that group. Mean ± SEM for CN-no SCeVD, CN-SCeVD, pADMCI-no SCeVD, and pADMCI-SCeVD, respectively, are 906 ± 24.6, 799 ± 43.6, 1076 ± 93.7, and 886 ± 81.0 pg/mL for CD81 (A), 232 ± 32.0, 1535 ± 140, 154 ± 36.5, and 1847 ± 341 pg/mL for type 1 large neutral amino acid transporter (LAT-1) (B), 510 ± 25.1, 1018 ± 30.7, 517 ± 30.0, and 1078 ± 45.6 pg/mL for type 1 glucose transporter (Glut-1) (C), and 1040 ± 266, 9499 ± 1167, 1204 ± 372, and 8056 ± 1417 pg/mL for permeability-glycoprotein (P-gp) (D). The significance of differences shown between values for CN-no SCeVD and CN-SCeVD and between values for pAD/MCI-no SCeVD and pAD/MCI-SCeVD, respectively, were calculated by an unpaired Student’s t test; **P < .0001

FIGURE 2

EDE levels of amyloid peptides and the putative amyloid peptide receptor protein PrPc in cognitively normal group without SCeVD (CN-no SCeVD), cognitively normal group with SCeVD (CN-SCeVD), pAD/MCI group without SCeVD (pAD/MCI-no SCeVD), and pAD/MCI group with SCeVD (pAD/MCI-SCeVD). Each point represents the value for one participant and the horizontal line in point clusters is the mean level for that group. Mean ± SEM for CN-no SCeVD, CN-SCeVD, pAD/MCI-no SCeVD and pAD/MCI-SCeVD, respectively, are 146 ± 13.7, 167 ± 22.6, 154 ± 15.5, and 257 ± 28.7 pg/mL for Aβ40 (A), 35.8 ± 4.77, 74.6 ± 19.4, 38.2 ± 5.04, and 153 ± 35.8 pg/mL for Aβ42 (B), 7376 ± 774, 15,899 ± 2636, 6461 ± 851, and 29,797 ± 4417 pg/mL for PrPc (C), and 136 ± 13.6, 245 ± 9.5, 75.3 ± 10.7 (n = 32), and 151 ± 20.1 (n = 30) pg/mL for P-181T-tau (D). The significance of differences shown between values for CN-no SCeVD and CN-SCeVD and between values for pAD/MCI-no SCeVD and pAD/MCI-SCeVD, respectively, were calculated by an unpaired Student’s t test; *P < .01, **P < .001