Beginning with passive immunization to screen antibodies, the antibody that emerged as most efficacious was poorly reactive to lipidated forms of apoE3 or apoE4. of AD is by modulating the deposition of A. Antibodies against nonlipidated apoE emerge as new biotherapies for AD prevention The study by Liao and colleagues evaluated a series of antibodies against human apoE (9). Through careful analysis they determined that antibodies against a nonlipidated, possibly aggregated, form of apoE4 are highly effective in delaying the deposition of A peptides in mice that express human mutant amyloid precursor protein (APP), human mutant presenilin (PS1), and human apoE4. Beginning with passive immunization mTOR inhibitor-2 to screen antibodies, the antibody that emerged as most efficacious was poorly reactive to lipidated forms of apoE3 or apoE4. Using adeno-associated virusCmediated CNS expression of recombinant antibodies, the authors show that Fc receptorCmediated clearance of the nonlipidated apoE4 was critical in delaying A deposition. Passive immunization with antibodies that recognized the lipidated forms of apoE was ineffective, due partially to binding to lipidated apoE in plasma and rapid clearance of the immune complex. The antibodies to nonlipidated apoE4 were highly reactive to cored-neuritic plaques in the APP/PS1 mice, suggesting that the nonlipidated protein closely associates with mTOR inhibitor-2 A aggregates. Thus, the presumptive mechanism by which these antibodies delay the deposition of A is through mTOR inhibitor-2 microglial-mediated phagocytosis of APOE4/A complexes that form early in the formation of A deposits (Figure 1). Whether these antibodies could be effective in promoting the clearance of preexisting A deposits requires further investigation. Open in a separate window Figure 1 Antibodies stimulate phagocytosis of apoE/A 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 A 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 A that ultimately seed the formation of pathological A deposits. Antibodies that selectively bind the nonlipidated apoE opsonize the apoE/A conglomerates, leading to phagocytosis and degradation by resident microglia. Whether nonlipidated apoE is an active or passive accomplice in the deposition of A is unclear. Studies in transgenic mice have generally shown that apoE plays a pivotal role in A deposition. Targeted inactivation of the endogenous allele in mice that overexpress mutant APP profoundly inhibits A deposition (10). Targeted replacement of endogenous alleles with human alleles has demonstrated that the allele is significantly more amyloidogenic than the or alleles (11, 12). More recently, a pair of studies demonstrated that apoE is critical in the early stages of A oligomerization and assembly, showing much less influence once deposition has taken hold (13, 14). Most effort in the field has focused on the lipidated forms of apoE. Studies have shown that lipidated apoE4 preferentially stabilizes A oligomers (15), selectively promotes A fibrillization (16, 17), and has a greater affinity for A peptides (2, 18). Early studies with recombinant apoE isolated from reported that nonlipidated apoE may interfere with A fibrillogenesis in vitro (19). However, studies in which ATP-binding cassette transporter A1 (ABCA1), a key cholesterol transporter in apoE lipidation, has been inactivated in mutant APP mice suggested that poorly lipidated murine apoE was associated with more severe A deposition (20). Moreover, the effect of ABCA1 deletion in APP/PS1/APOE4 mice on A deposition was more severe than the effect of ABCA1 deletion in APP/PS1/APOE3 mice (21). If nonlipidated apoE4 is an active accomplice in promoting A deposition, and if this isoform of apoE is indeed more prone to escape lipidation, then one might predict that transgenic overexpression of human in mutant APP or APP/PS1 mice should dramatically worsen A pathology. However, 2 separate studies using different transgenic approaches did not show that overexpression of human exacerbated A deposition (22, 23). Thus, although the evidence is clear that poor lipidation of apoE4 is associated with more severe A deposition, it is still not entirely clear whether this effect is due to an active role of nonlipidated protein in promoting amyloidogenesis, or due to diminished abilities of poorly lipidated protein to participate in the clearance of Rabbit Polyclonal to NRIP3 A in the CNS (mechanisms reviewed in ref. 8). Summary and future directions Whether nonlipidated apoE4 is an active or passive accomplice does not diminish the potential utility of targeting this particular species of apoE by immune therapy if removing it also removes the initial assemblies of A that are the culprit in initiating A deposition. One advantage.
