Rolle des humanen Apolipoprotein E im angeborenen Immunsystem
Research on age-related diseases like arteriosclerosis, dementia and age-related macular degeneration (AMD) is playing an important role in our steadily aging society. A conspicuous feature of many of these diseases is their association with the apolipoprotein E (ApoE). ApoE is an important protein in lipid metabolism and binds lipids as well as lipid receptors. Three isoforms, ApoE2, ApoE3 and ApoE4 differ only by one or two amino acids. Carriers of the ApoE2 isoform have an increased risk to develop AMD wheres the ApoE4 isoform is associated with a higher risk to develop dementia and arteriosclerosis. The cause of this is currently unknown. ApoE is found mainly in the deposits characteristic for the diseases. The deposits consist to a large extent of lipids, amyloid beta and cell debris, and form an activator surface for the complement system. An important role of the complement system is to eliminate body-borne waste products anti-inflammatorily, such as dead and damaged cells or modified lipids, with the help of regulators. However, in the case of the disease-related deposits, overactivation of the complement system, permanent inflammation and local damage occur. An association of the ApoE isoforms with the complement system has not yet been investigated. For the first time, this thesis shows that ApoE inhibits the classical pathway of the complement system at the level of the initial phase. Thus, ApoE is a new regulator of this pathway. All ApoE isoforms bind to the N-terminal domain between amino acids 139 and 152 to C1q. ApoE does not compete with the C1s-C1r-C1r-C1s tetramer to bind to C1q, but prevents the proteolytic cleavage of C2 and C4 by the C1 complex. According to that, ApoE has a double function: it acts as a lipid transport molecule and at the same time as a regulator of the classical complement pathway. Complement-activating surfaces, such as oxidized lipids which bind C1q, can thus be eliminated anti-inflammatorily with the aid of ApoE.
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