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. 2020 Jul;22(1):227-238.
doi: 10.3892/mmr.2020.11118. Epub 2020 May 5.

Elevated plasma levels of exosomal BACE1‑AS combined with the volume and thickness of the right entorhinal cortex may serve as a biomarker for the detection of Alzheimer's disease

Dewei Wang  1 , Ping Wang  1 , Xianli Bian  1 , Shunliang Xu  1 , Qingbo Zhou  1 , Yuan Zhang  2 , Mao Ding  1 , Min Han  3 , Ling Huang  4 , Jianzhong Bi  1 , Yuxiu Jia  5 , Zhaohong Xie  1
Affiliations

Elevated plasma levels of exosomal BACE1‑AS combined with the volume and thickness of the right entorhinal cortex may serve as a biomarker for the detection of Alzheimer's disease

Dewei Wang et al. Mol Med Rep. 2020 Jul.

Abstract

Long non-coding RNA (lncRNA) and exosomes are involved in the pathological process of Alzheimer's disease (AD), the pathological changes of which are usually first observed in the entorhinal cortex and hippocampus. The aim of the present study was to determine whether the measurement of plasma exosomal lncRNA combined with image data of the entorhinal cortex and hippocampus could be used as a biomarker of AD. A total of 72 patients with AD and 62 controls were recruited, and the expression levels of several lncRNAs were assessed. Of the recruited participants, 22 patients and 26 controls received brain 3D‑BRAVO sequence magnetic resonance imaging (MRI) scans, which were analyzed using an automated analysis tool. The plasma exosomal β‑site amyloid precursor protein cleaving enzyme‑1‑antisense transcript (BACE1‑AS) levels in patients with AD were significantly higher compared with the controls (P<0.005). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) was 0.761 for BACE1‑AS, the sensitivity was 87.5%, and the specificity was 61.3%. Analysis of MRI images indicated that the right entorhinal cortex volume (P=0.015) and thickness (P=0.022) in patients with AD were significantly smaller. The AUC was 0.688 for the right entorhinal cortex volume, with a sensitivity of 59.1%, and the specificity was 84.6%. The AUC was 0.689 for right entorhinal cortex thickness, with a sensitivity of 80.8%, and the specificity was 59.1%. A series‑parallel test which integrated the BACE1‑AS with the right entorhinal cortex volume and thickness, raised the specificity and sensitivity to 96.15 and 90.91%, respectively. A logistic regression model demonstrated that combination of the 3 indices provided improved sensitivity and specificity simultaneously, particularly when adjusting for age and sex (AUC, 0.819; sensitivity, 81%; specificity, 73.1%). The results of the present study demonstrated that detection of plasma exosomal BACE1‑AS levels combined with the volume and thickness of the right entorhinal cortex may be used as a novel biomarker of AD.

Keywords: alzheimer's disease; exosome; β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; biomarker; entorhinal cortex.

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Figures

Figure 1.
Figure 1.
Characterization of plasma exosomes. (A) Western blot analysis of exosomal surface marker proteins (ALIX and CD63). (B) Exosomes exhibited spherical nanoparticles and had a diameter ranging between 30–150 nm under transmission electron microscopy (magnification, ×10,000). The arrow shows an exosome that was 100 nm in diameter. Scale bar=200 nm. (C) Particle size distribution and relative concentration of exosomes measured by Nanoparticle Tracking Analysis. ALIX, apoptosis-linked gene 2-interacting protein X; CD, cluster of differentiation; BACE1-AS, β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; BC200, brain cytoplasmic 200; FWHM, full width at half maximum; AD, Alzheimer's disease.
Figure 2.
Figure 2.
Validation of candidate RNAs (lncRNA BACE1-AS, BC200, 51A and BACE1 mRNA) in plasma exosomes of patients with AD and controls. The expression levels of the 4 RNAs were analyzed by reverse transcription-quantitative polymerase chain reaction and normalized by GAPDH. The bars indicated median with interquartile range. (A) The expression levels of BACE1-AS increased in AD compared with the control group. (B-D) Levels of BACE1 mRNA, BC200 and 51A had no significant differences between two groups. **P<0.05 vs. the control group. lnc, long noncoding; BACE1-AS, β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; BC200, brain cytoplasmic 200; AD, Alzheimer's disease.
Figure 3.
Figure 3.
Correlation analyses between expression levels of BACE1-AS and clinical data. P-values and r values are presented in each graph. (A) BACE1-AS vs. blood levels of TG; (B) BACE1-AS vs. blood levels of TC; (C) BACE1-AS vs. blood levels of HDL-C; (D) BACE1-AS vs. age; (E) BACE1-AS vs. blood levels of Hb; (F) BACE1-AS vs. the onset time of AD; (G) BACE1-AS vs. scores of MMSE for AD patients. P<0.05 was considered to indicate a statistically significant difference. There were no significant correlations in all (A-G, P>0.05). AD, Alzheimer's disease; BACE1-AS, β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; TG, triglyceride; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; Hb, hemoglobin; r, Spearman's rank correlation coefficient; MMSE, Mini Mental State Examination.
Figure 4.
Figure 4.
ROC curves of (A) BACE1-AS, (B) BACE1 mRNA, (C) BC200 and (D) 51A for diagnosis of Alzheimer's disease. (E) Combined ROC curves of the four. AUC, 95% CI and P-values were presented in graphs. ROC, receiver operating characteristic; BACE1-AS, β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; BC200, brain cytoplasmic 200; AUC, area under the curve; CI, confidence interval.
Figure 5.
Figure 5.
The diagnostic value of MRI indices and combined detection with BACE1-AS. (A and B) The right entorhinal cortex volume and right entorhinal cortex mean thickness in AD patients were significantly lower than in controls. (C and D) There were no significant correlations between the right entorhinal cortex volume, mean thickness of the right entorhinal cortex and BACE1-AS, respectively, in 48 participants. (E) The ROC curves of right entorhinal cortex volume, right entorhinal cortex mean thickness, BACE1-AS and combined diagnostic index based on a regression model (adjusted age and sex). (F) The axial, coronal and sagittal positions of brain MRI of a subject from left to right, with the yellow area being the hippocampus and the green area being the entorhinal cortex. *P<0.05 vs. the control group. MRI, magnetic resonance imaging; BACE1-AS, β-site amyloid precursor protein cleaving enzyme-1-antisense transcript; ROC, receiver operating characteristic; AD, Alzheimer's disease.
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