Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation

Abstract

The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD.

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

“…This finding provides a mechanistic explanation to the observed formation of more amorphous assemblies here shown by TEM and also a possible route of formation to the circulating complexes between ApoE and Aβ found in vivo . Inhibiting ApoE binding may also provide a mechanistic explanation to the recent findings where a beneficial effect is observed after injection of anti‐ApoE4 antibodies into AD mouse model as well as peptides having the ability to interfere with the ApoE‐Aβ interaction .…”

“…Although the involvement of ApoE in the process of AD is a multifactorial process, these findings might present an explanation for the beneficial effect noted from ApoE knockout studies where ApoE rather is suggested to be a pathological chaperone. Inhibiting ApoE binding may also provide a mechanistic explanation to the recent findings where a beneficial effect is observed after injection of anti‐ApoE4 antibodies into AD mouse model . Based on these results, interfering with ApoE binding and its ability to prevent elongation might reduce a population of potentially more toxic Aβ assemblies and serve as an interesting therapeutic target.…”

High‐density lipoprotein mimetic peptide 4F mitigates amyloid‐β‐induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia

“…In contrast, apoE KO AD mice have reduced amyloid deposition (Bales et al 1997;Irizarry et al 2000) and tau pathology (Shi et al 2017). Furthermore, immunotherapy against apoE was associated with reduced Ab deposition in AD mice (Kim et al 2012), an effect that has recently been recapitulated using an antibody targeting only non-lipidated forms of apoE (Liao et al 2018). These findings, together, indicate that the lipidation state of apoE may influence AD pathology more so than the absolute level of apoE.…”

“…), an effect that has recently been recapitulated using an antibody targeting only non‐lipidated forms of apoE (Liao et al . ). These findings, together, indicate that the lipidation state of apoE may influence AD pathology more so than the absolute level of apoE.…”

Setbacks and promises for drugs against Alzheimer's disease

“…Two of the running Alzheimer's programs target BACE1-an aspartic protease that initiates the formation of Ab from APP-and TREM2, an immune receptor found in brain microglia that has been linked to the risk of developing Alzheimer's. Moreover, a recent study resulting from a collaboration between Denali and Washington University School of Medicine in St Louis, MS, USA, showed that an antibody targeting the apoE protein found in brain plaques cuts the level of plaques by half, raising hopes that this could limit the debilitating symptoms of the disease [5]. The researchers expressed the human APOE gene-variants of which are considered the most significant risk factor for AD-in APOE-knocked mice.…”