Einfluss von Anti-NMDA-Rezeptor-NR1-Autoantikörpern bei ApoE4-bedingter chronischer Beeinträchtigung der Blut-Hirn-Schranke

Role of anti-NMDA-receptor NR1 autoantibodies depending on ApoE4 related chronic impairment of the blood brain barrier

by Maria Zerche
Doctoral thesis
Date of Examination:2018-07-19
Date of issue:2018-07-18
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Dr. Jan Liman
Referee:Prof. Dr. Thomas Meyer
Persistent Address: http://dx.doi.org/10.53846/goediss-6967

 

 

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Abstract

English

Anti-N-methyl-D-aspartate-receptor subunit 1 autoantibodies (NMDAR-NR1-AB) have mainly been described in context of central nervous system (CNS) pathologies. In contrast, recent studies reported high seroprevalence of NMDAR-NR1-AB in both healthy and neuropsychiatrically ill subjects. It was hypothesized that this might be due to the significance of the blood-brain barrier (BBB) for both development and potential effects of CNS-reactive AB. Apolipoprotein E4 (ApoE4) represents a genetic risk factor for a chronically impaired BBB. Therefore, the present study investigates the role of NMDAR-NR1-AB depending on ApoE4-related chronic impairment of the BBB. ApoE genotype and NMDAR-NR1-AB seropositivity were determined in a cohort of 2492 neuropsychiatric patients and healthy control subjects as well as a second cohort of 464 patients with acute ischemic stroke of the middle cerebral artery. A high seroprevalence of NMDAR-NR1-AB independent of disease status could be replicated and extended to older age groups. The interaction of APOE4 carrier status and NMDAR-NR1-AB seropositivity was found to be significantly associated with the diagnosis of schizoaffective disorder. In patients with acute ischemic stroke, pre-existing NMDAR-NR1-AB were found to modulate the evolution of lesion size in diffusion-weighted magnetic resonance imaging (DW-MRI). The present results demonstrate the importance of BBB integrity for the influence of NMDA-NR1-AB. Both projects provide evidence of ApoE4-related chronic BBB disruption mediating pathological NMDAR-NR1-AB effects not occurring in patients with an intact BBB. Furthermore, first data for beneficial effects of circulating CNS-reactive AB is provided supporting the concept of physiological autoimmunity.
Keywords: Anti-NMDA-receptor subunit 1 autoantibodies; ApoE4; blood brain barrier; schizoaffective disorder; ischemic stroke
Schlagwörter: Anti-NMDA-Rezeptor-NR1-Autoantikörper; ApoE4; Blut-Hirn-Schranke; Schizoaffektive Störung; Ischämischer Schlaganfall
 
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