An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo

Abstract

ApolipoproteinE4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and as such is a promising therapeutic target. This study examined the extent to which the pathological effects of apoE4 can be counteracted in vivo utilizing an immunological approach in which anti-apoE4 antibodies are applied peripherally by i.p. injections into apoE4-targeted replacement mice. Prerequisites for the successful pursuit of this objective are the availability of antibodies that specifically bind brain apoE4 and not apoE3, and demonstrating that direct application of these antibodies into the brain can counteract the effects of apoE4. Accordingly, it was shown that the antiapoE4 monoclonal antibody (mAb) 9D11 binds specifically to brain apoE4 and not apoE3. Direct i.c.v. application of mAb 9D11 prevented the apoE4-driven accumulation of Aβ in hippocampal neurons following activation of the amyloid cascade by inhibiting the Aβ-degrading enzyme neprilysin. These findings provide a proof-of-concept that anti-apoE4 mAb 9D11, when introduced into the brain, can counteract the apoE4 effects in vivo. Subsequent experiments, utilizing repeated i.p. injections of mAb 9D11, resulted in the formation of apoE/IgG complexes specifically in apoE4 mice. This was associated with reversal of the cognitive impairments of apoE4 in the Morris water maze and the novel object recognition test as well as with reversal of key apoE4-driven pathologies including the hyperphosphorylated tau and the reduced levels of the apoER2 receptor. These results indicate that anti-apoE4 immunotherapy counteracts the cognitive and brain pathological effects of apoE4, and suggest that such an approach could also benefit human apoE4 carriers.

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.…”

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…Endogenous mouse APOE was replaced by either human APOE3 or APOE4, in order to create APOE-TR mice by gene targeting as previously described [101]. These mice were purchased from Taconic (Germantown, NY, USA), and were backcrossed at Taconic for eight generations after their preparation.…”

Molecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease

“…This reveals that repetitive intraperitoneal injection of these antibodies in mice leads to their aggregation in the brain and also in the generation of APOE/IgG complexes, especially in APOE4 mice. Moreover, this was connected with the restoration of cognitive damages in APOE4 mice as well as with the restoration of central synaptic and AD-associated pathological effects of APOE4 [131]. .…”

“…Despite the mode of actions involving these pivotal effects of the anti-APOE monoclonal antibodies, these outcomes have an enormous significance and offer a fundamental idea about the reliability of anti-APOE4 immunotherapy as a promising therapeutic strategy. Furthermore, this strategy has now been expanded to APOE3-and APOE4directed mice using an antibody that reacts particularly with APOE4 [131]. This reveals that repetitive intraperitoneal injection of these antibodies in mice leads to their aggregation in the brain and also in the generation of APOE/IgG complexes, especially in APOE4 mice.…”