The complement system has an important role in neuroinflammation, both in the pathogenesis of Alzheimer’s disease and in the most severe infections affecting the central nervous system such as bacterial meningitis and neuroborreliosis. Neuroinflammation related to both of these diseases are not well understood and the patients affected have equally poor prognosis as two decades ago. This indicates that we still don’t fully understand the complex pathways that leads to neuronal damage in bacterial infections or neurodegenerative diseases.
Our group was the first to discover the interaction between the Alzheimer’s disease associated apolipoprotein E (apoE) and complement regulator factor H and the role of this interaction in reducing complement mediated inflammation on high-density lipoproteins (HDL). The most recent publication of the group describes a mechanism by which apoE isoform-specific interaction between apoE and factor H could alter neuroinflammation in Alzheimer’s disease. In addition, our studies on pneumococcal toxins have shown that upon infection these may trigger vascular damage, modify HDL particles that are important in reducing inflammation in atherosclerosis patients.
The main aims of our research is to understand (1) The target specificity Amyloid-β (Aβ) (2) how complement and innate-immunity alter clearance of the Aβ trapped targets (3) whether pathological molecules/structures (such as modified human molecules and molecule complexes) or microbes escape the toxic Aβ peptide and thereby may play a role in disease pathology (4), the molecular mechanisms how complement activation and regulation play a role in synapse loss in Alzheimer’s disease (5) and how complement regulation and immune defense play a major role in high-risk cardiovascular disease.
A) Complement is activated trough three pathways leading to C3b opsonization, release of anaphylatoxins (C5a) and formation of membrane attack complexes (MAC). Factor H (FH) regulates complement at the C3b level (B) through binding to apoE on Aβ deposits (structure of C3b: PDB 5FO7) (Chernyaeva, Ratti et al. 2023). (C) Structural model for apoE2-FH complex (apoE yellow, receptor-binding domain grey, FH domains 5-7 green) (Chernyaeva, Ratti et al. 2023). (D) Borrelia sp. expresses FH-binding proteins such as FhbA (green) to escape from the complement (Kogan, Haapasalo et al. 2022).