Xiong M, Jiang H, Serrano JR, Gonzales ER, Wang C, Gratuze M, Hoyle R, Bien-Ly N, Silverman AP, Sullivan PM, Watts RJ, Ulrich JD, Zipfel GJ, Holtzman DM. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med. 2021 Feb 17;13(581) PubMed.

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  1. This an impressive and important paper. Key to this study is the development of the HAE-4 anti-ApoE antibody and its specificity for poorly lipidated forms of ApoE, which are preferentially incorporated into amyloid plaques. The study is the quintessential product of the Holtzman lab, with expert experimental design, unambiguous outcomes, and clinically relevant conclusions.

    There are a number of interesting findings. Notably, the chi-Adu is remarkably ineffective in this model in reducing plaque burden and CAA, while inducing microhemorrhages. Conversely, HAE-4 is effective at reduction of CAA as well as parenchymal plaques, with restoration of vascular function. The absence of an effect of chi-Adu on plaque load is different from its reported effect in clinical trials and prior animal studies, suggesting that the 5XE4 model may not faithfully model all aspects of the amyloid pathology, or that the actions of the chimeric antibody are distinct.  

    Overall, the paper provides a clear rationale to pursue anti-ApoE based immunotherapy.

    View all comments by Gary Landreth

  2. This paper by Monica Xiong and colleagues elegantly demonstrates how anti-human ApoE immunotherapy efficiently reduced vascular and parenchymal amyloid deposits in the 5XFAD model expressing human ApoE4, whereas an anti-Aβ immunotherapy had no effect on cerebral amyloid angiopathy (CAA). Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, whereas the anti-ApoE antibody didn’t stimulate microhemorrhages or rescue cerebrovascular dysfunction.

    This is particularly relevant considering the disappointing outcomes of anti-Aβ immunotherapy clinical trials that resulted in ARIA, brain edema, and hemorrhages. Therefore, developing a therapeutic approach that safely removes amyloid accumulation not only from the parenchyma but also from the vasculature holds great promise for a possible treatment.

    This study not only supports the development of anti-ApoE immunotherapy to safely reduce amyloid levels, but also opens the possibility of investigating antibody-based therapies targeting other known proteins closely associated with amyloid in CAA and AD.

    Despite that, for the moment there isn’t a clear understanding of the mechanism by which this ApoE antibody safely removes CAA without stimulating microhemorrhages. This study underscores the importance of “the right amount” of inflammatory response associated with the treatment. It has to be strong enough to have an effect over amyloid load, but not strong enough to overstimulate an immune response detrimental to the vasculature. It’s necessary to determine this “right amount” of inflammatory response to further understand the dynamic immune response associated to AD.

    On a similar point, future studies should focus not only on understanding the mechanisms involved in the immune response associated with amyloid plaques in AD but also with CAA.  Interestingly, the authors showed how the anti-Aβ immunotherapy stimulated reactive astrocytes around CAA, which correlated with microhemorrhage severity, but very little reactive microglia, suggesting that proinflammatory cytokines known to stimulate astrogliosis may originate from another source different than microglia.

    Interestingly, we recently demonstrated in a mouse model for CAA an increased activation of neurotoxic astrocytes associated to vascular amyloid deposits, but not major microglia reactivity (Taylor et al., 2020), suggesting as well that, in the context of CAA, proinflammatory cytokines known to stimulate astrogliosis may originate from another source. This supports the notion that the glia response associated to CAA-amyloid differs from the one associate to plaques in AD.

    References:

    Taylor X, Cisternas P, You Y, You Y, Xiang S, Marambio Y, Zhang J, Vidal R, Lasagna-Reeves CA. A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy. J Neuroinflammation. 2020 Jul 25;17(1):223. PubMed.

    View all comments by Cristian Lasagna-Reeves

  3. The Holtzman group's anti-ApoE antibody (HAE-4) recognizes human ApoE4 and ApoE3. This antibody binds specifically to non-lipidated human ApoE4 and ApoE3 and, when delivered to ApoE4-expressing mice, reduces Aβ deposition (Liao et al., 2018). These findings are now extended by the current paper, which shows that, unlike established anti-Aβ mAb, HAE- 4 also reduces cerebral amyloid angiopathy (CAA) and does not exacerbate microhemorrhages. These results suggest that targeting APOE in the core of both CAA and senile plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.

    Since HAE-4 binds similarly to non-lipidated ApoE4 and ApoE3, it will be of great interest to assess the extent to which the HAE-4 driven immunotherapy is also apparent in non-ApoE4 carriers. This is particularly important as about half of AD patients are not ApoE4 carriers.

    It is generally agreed that the pathological effects of ApoE4 are divided into Aβ-related and Aβ-independent mechanisms, and that ApoE4 is hypolipidated relative to the AD benign isoform ApoE3. Accordingly, it would be of interest to examine whether the ApoE4 epitope recognized by HAE-4 also plays a role in mediating non Aβ-related effects of ApoE4, such as downregulation of distinct receptors by ApoE4 in primary neuronal cultures.

    References:

    Liao F, Li A, Xiong M, Bien-Ly N, Jiang H, Zhang Y, Finn MB, Hoyle R, Keyser J, Lefton KB, Robinson GO, Serrano JR, Silverman AP, Guo JL, Getz J, Henne K, Leyns CE, Gallardo G, Ulrich JD, Sullivan PM, Lerner EP, Hudry E, Sweeney ZK, Dennis MS, Hyman BT, Watts RJ, Holtzman DM. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018 May 1;128(5):2144-2155. Epub 2018 Mar 30 PubMed.

    View all comments by Daniel Michaelson

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