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Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.
Methods: MOG\(_{35-55}\) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.
Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE\(^{-/-}\)) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE\(^{-/-}\) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naive animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.
Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.
Die Beurteilung der Angemessenheit theoretischer Oberlegungen auf der Grundlage statistischer Hypothesentests ist für die empirische Forschung von zentraler Bedeutung. Im Mittelpunkt der Arbeit stehen die mit der Testung von multivariaten Strukturgleichungsmodellen (LISREL-Modelle) verbundenen Probleme. Zu Beginn wird das LISREL-Modell unter den Aspekten der simultanen Analyse von Kovarianzund Mittelwertstrukturen und der Modelltestung diskutiert. Anschließend werden anhand eines Illustrationsbeispiels aus der pädagogisch-psychologischen Forschung verschiedene Vorgehensweisen der Kreuzvalidierung einander gegenübergestellt und an empirischen Daten demonstriert. Es zeigt sich, daß die Obernahme exakter numerischer Parameterwerte sowohl aufgrund inhaltlicher wie auch formaler Argumente unangemessen streng erscheint. Diese Einschätzung kann empirisch belegt werden, indem eine Approximation von Intervallrestriktionen vorgenommen wird.