Relationship between Brain Tissue Changes and Blood Biomarkers of Cyclophilin A, Heme Oxygenase-1, and Inositol-Requiring Enzyme 1 in Patients with Alzheimer's Disease.

Hyon-Il Choi,Chang-Woo Ryu,Jiyoon Lee,Wonchae Choe,Woo-In Lee,Kiyoon Kim,Soonchan Park,Hak Young Rhee,Geon-Ho Jahng,Yunjung Chang

doi:10.3390/diagnostics11050740

Hyon-Il Choi, Chang-Woo Ryu + Show 8 more

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https://doi.org/10.3390/diagnostics11050740

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Abstract

Cyclophilin A (CypA), heme oxygenase-1 (HO-1), and inositol-requiring enzyme 1 (IRE1) are believed to be associated with Alzheimer’s disease (AD). In this study, we investigated the association between gray matter volume (GMV) changes and blood levels of CypA, HO-1, and IRE1 in cognitively normal (CN) subjects and those with amnestic mild cognitive impairment (aMCI) and AD. Forty-five elderly CN, 34 aMCI, and 39 AD subjects were enrolled in this study. The results of voxel-based multiple regression analysis showed that blood levels of CypA, HO-1, and IRE1 were correlated with GMV on brain magnetic resonance imaging (MRI) in the entire population (p = 0.0005). The three serum protein levels were correlated with GMV of signature AD regions in the population as a whole. CypA values increased with increasing GMV in the occipital gyrus (r = 0.387, p < 0.0001) and posterior cingulate (r = 0.196, p = 0.034). HO-1 values increased with increasing GMV at the uncus (r = 0.307, p = 0.0008), lateral globus pallidus and putamen (r = 0.287, p = 0.002), and hippocampus (r = 0.197, p = 0.034). IRE1 values decreased with increasing GMV at the uncus (r = −0.239, p = 0.010) and lateral globus pallidus and putamen (r = −0.335, p = 0.0002). Associations between the three serum protein levels and regional GMV indicate that the blood levels of these biomarkers may reflect the pathological mechanism of AD in the brain.

Highlights

Alzheimer s disease (AD), the most common cause of dementia, is considered an inevitable consequence of aging that is exacerbated by a genetic predisposition
We evaluated the relationship between brain tissue volume changes as imaging biomarkers and cyclophilin A (CypA), heme oxygenase-1 (HO-1), and inositol-requiring enzyme 1 (IRE1) as blood biomarkers in cognitively normal (CN) elderly, Amnestic mild cognitive impairment (aMCI), and AD participants
The Korean (K)-Mini-Mental State Examination (MMSE) scores were significantly different between the three subject groups (F = 65.904, p < 0.001), as expected

Summary

Introduction

Alzheimer s disease (AD), the most common cause of dementia, is considered an inevitable consequence of aging that is exacerbated by a genetic predisposition. Three proteins in the plasma are associated with neurotoxicity induced by ER stress and oxidative damage: cyclophilin A (CypA), heme oxygenase-1 (HO-1), and inositol-requiring enzyme 1 (IRE1) These three proteins may have an association with AD pathogenesis and are potential blood-borne biomarkers. CypA, known as peptidylprolyl isomerase A (PPIA), has been shown to play a regulatory role in the maintenance of blood–brain barrier (BBB) integrity in the central nervous system via a complex with nuclear factor κB and matrix metalloproteinase 9 under control of apolipoprotein E (APOE) It can mediate BBB dysfunction in the presence of APOE4, a major genetic risk factor for AD [8,9]. An experimental model showed that UPR induction prevents iron accumulation and oligodendrocyte loss, which are shown in AD pathology [14]

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