Targeting the accomplice to thwart the culprit: a new target for the prevention of amyloid deposition

Abstract

Inheritance of the E4 allele of the apolipoprotein E gene (APOE4) substantially increases the risk of developing late-onset Alzheimer disease (AD). A large body of evidence has firmly established a role for apoE in modulating the risk of developing the amyloid plaque pathology that is pathognomonic for AD. In this issue of the JCI, Liao and colleagues discovered that antibodies against a nonlipidated form of apoE4 are highly effective in delaying the deposition of amyloid β (Aβ) peptides in mouse models of AD pathology. Using a combination of passive immunization and viral-mediated expression of recombinant antibodies, the authors show that Fc receptor-mediated clearance of the nonlipidated apoE4 was critical in delaying Aβ deposition. Collectively, this study identifies a new therapeutic target that could be exploited to prevent, or possibly reverse, the Aβ pathology of AD.

Figure 1. Antibodies stimulate phagocytosis of apoE/Aβ conglomerates to slow the formation of pathological amyloid deposits.

Through the action of the ATP-binding cassette transporter A1 (ABCA1) most apoE acquires lipid in the Golgi and is secreted as proteolipid particles that bind monomeric Aβ and facilitate clearance through multiple pathways. A small fraction of apoE, particularly apoE4, fails to assemble into proteolipid particles and is prone to bind assemblies of Aβ that ultimately seed the formation of pathological Aβ deposits. Antibodies that selectively bind the nonlipidated apoE opsonize the apoE/Aβ conglomerates, leading to phagocytosis and degradation by resident microglia.