Apolipoprotein E (ApoE) has been implicated in atherosclerosis, Alzheimer`s disease, cancer and other prototypical chronic inflammatory diseases. However, a common mechanisms of action of ApoE in inflammation has not been identified. C1q is the initiating molecule of the classical complement cascade, which contributes to a broad range of inflammatory diseases by producing powerful chemotactic anaphylatoxins and other immune mediators. DZHK scientists and their colleagues together with collaborators showed that two molecules, which had previously been thought to act as independent mediators of inflammation, i.e. C1q and ApoE, form a protein-protein complex in atherosclerosis and Alzheimer`s disease. These data directly tie ApoE to the regulation of the immune system and identify its mechanism of action.
In collaboration with DZNE scientists, Yin and his colleagues examined brain samples of 30 patients with various degrees of AD pathologies. Surprisingly, the choroid plexus, which produces the cerebrospinal fluid and is the major gateway for inflammatory leukocytes to enter the brain, appeared to be involved in Alzheimer`s disease pathology: Choroid plexuses of patients afflicted with Alzheimer`s disease showed significant lipid deposits. Importantly, the lipid burden in the choroid plexus correlated with Alzheimer`s disease pathologies in the brain, the ApoE4 isoform, and cognitive decline. These data in human brains were corroborated in the choroid plexus of aged ApoE-/- and ApoE4 transgenic mice, which suggested that a combination of hyperlipidemia and the ApoE4 isoform trigger brain inflammation via choroid plexus lipid-triggered inflammatory pathway. It is noteworthy that both hyperlipidemia and the ApoE4 isoform are well established risk factors for atherosclerosis. Therefore, these data indicate that Yin et al. identified a longsought link between risk factors of atherosclerosis and Alzheimer´s disease.
C1q-ApoE complexes were prominent around human choroid plexus lipid deposits, in Alzheimer`s disease plaques, and human carotid atherosclerotic lesions. The number of C1q-ApoE complexes were therefore associated with disease severity in diseases as varied as atherosclerosis and Alzheimer´s disease. As C1q-ApoE complexes indicated ongoing complement activity in vivo, Yin et al. data studied the effect of complement inhibition on atherosclerosis, choroid plexus inflammation, and Alzheimer`s disease in various mouse models: siRNA directed against complement C5, i.e. the downstream inflammatory mediator and anaphylatoxin of all three complement cascades, attenuated choroid plexus inflammation, Aβ plaque-associated microglia cell numbers, and atherosclerotic plaque burden. Therefore, ApoE qualifies as a direct checkpoint inhibitor of two prototypic and clinically significant inflammatory diseases while reducing C5 attenuates disease severity.