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Marino C, Perez-Corredor P, O'Hare M, Heuer A, Chmielewska N, Gordon H, Chandrahas AS, Gonzalez-Buendia L, Delgado-Tirado S, Doan TH, Vanderleest TE, Arevalo-Alquichire S, Obar RA, Ortiz-Cordero C, Villegas A, Sepulveda-Falla D, Kim LA, Lopera F, Mahley R, Huang Y, Quiroz YT, Arboleda-Velasquez JF. APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement. 2024 Feb;20(2):819-836. Epub 2023 Oct 4 PubMed.
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Washington University
Washington University
The identification of rare variants in APOE that appear to protect against Alzheimer’s disease, such as V236E (Jacksonville) and R136S (Christchurch), present an exciting opportunity to better understand the mechanisms by which APOE may influence different aspects of AD pathology and neurodegeneration. As the authors note, both the Jacksonville and Christchurch variants reduce the affinity of APOE for heparin sulfate proteoglycans (HSPGs), which could indicate a potential role for the APOE-HSPG interaction in AD pathogenesis. The antibodies described in the paper provide an excellent tool for blocking the HPSG binding region on APOE, and the authors report some interesting preliminary effects of the antibody in reducing tau phosphorylation in different experiments.
Directly translating an effect of an anti-APOE antibody to a therapy may turn out to be quite challenging. For example, our group has developed an APOE antibody (HAE-4) that reduces amyloid plaques, CAA, and amyloid-dependent tau seeding/spreading. This antibody targets a conformation of APOE that is co-deposited in amyloid plaques and CAA. Importantly, it does not bind to native, lipidated APOE particles in the plasma or CNS (Liao et al., 2018; Gratuze et al., 2022; Xiong et al., 2021). Because of this, the half-life of HAE-4 after peripheral injection is similar to that of other IgG’s in mice, about seven days, and because it does not bind lipidated APOE, it does not affect peripheral lipoprotein metabolism.
In contrast, we have found that most peripherally administered APOE antibodies recognize lipidated, physiological APOE-containing lipoproteins, and have a very short half-life, in the order of minutes to hours (Liao et al., 2018). Given the abundance of APOE in both the periphery and CNS, achieving a therapeutic level of HSPG-APOE neutralization in the brain could be a very tall order if the antibody used in the study by Marino et al. binds to lipidated APOE. It may not get to its target at a high enough concentration to neutralize it over longer periods of time. As such, it would be interesting to know if the HSPG-blocking APOE antibodies affected peripheral lipoprotein/lipid profiles similarly to the Christchurch variant.
Nonetheless, this study is an important step in leveraging the unique biology of the Christchurch APOE variant to gain a better understanding of how one might try to neutralize an APOE region that affects certain aspects of AD pathophysiology.
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.
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View all comments by David HoltzmanOHSU
The R136S Christchurch mutation is in the domain involved in the interaction between ApoE and heparan sulfate proteoglycans (HSPGs) which binds the low-density lipoprotein (LDL) and LDL receptor-related protein (LRP) receptors. The astrocyte-secreted HSPG called Glypican-4 (GPC-4) binds ApoE4 and mediates its toxicity to propagate tau pathology in the brain. E4-mediated surface trafficking of the APOE receptor LRP 1 through GPC-4 can be a gateway to spreading of tau pathology (Saroja et al., 2022). As previously reported for prion proteins, HSPGs are involved in the uptake of tau and α-synuclein fibrils, causing intracellular aggregation and transcellular aggregate propagation (Holmes et al., 2013).
Consistent with these data, in this study, Marino et al. provide support for the hypothesis that the protective effect of the APOE3 Christchurch (APOECh) variant against a dominant AD mutation is due to reduced interactions of ApoE with heparan sulfate proteoglycans (HSPGs). Introducing the Christchurch mutation in E4 reduced cytotoxicity in the lactate dehydrogenase assay of SH-SY5Y neuroblastoma cells treated for 24 hours compared to those treated with E4.
Well-characterized ApoE-binding antibodies that specifically inhibit the interaction of ApoE with HSPGs reduced ApoE-induced tau pathology in the retina of MAPT*P301S mice three days after intravitreal injection of E3. Notably, the paraformaldehyde fixation of the retina was overnight at 4ºC, while typically much shorter fixation times are being used for retina immunohistochemistry to improve the signal-to-noise ratio. Intraperitoneal administration of these well-characterized ApoE-binding antibodies that inhibit the interaction of ApoE with HSPGs also reduced phosphorylation of tau S396 in the brain. Cognitive performance was not addressed in this study but would be expected to be improved with reduced tau pathology.
While the authors provide evidence that these antibodies, when labeled with Alexa-647, can penetrate the blood-brain barrier, this might not be required to reduce tau pathology. Liver-generated human ApoE does not enter the brain, but murine ApoE and markers of synaptic integrity, neuroinflammation, and insulin signaling are negatively affected in the brains of human liver E4 mice (Giannisis et al., 2022). Comparing human liver E3 with targeted replacement E3 mice, there are model-dependent correlations between plasma ApoE levels and behavioral and cognitive measures, suggesting that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes (Kessler et al., 2023).
Consistent with a role of the liver in brain phenotypes is the neurodegenerative phenotype described in mice that generate human Aβ only in the liver (Lam et al., 2021), the altered levels of Aβ-degrading enzymes in the livers of AD patients (Maarouf et al., 2018), and the association between altered liver enzymes and AD diagnostic, cognition, neuroimaging, and cerebrospinal fluid biomarkers (Nho et al., 2019). Further, a recent study showed that inhibition of liver enzyme soluble epoxide hydrolase drives a subsequent increase of 14,15-epoxyeicosatrienoic acid in the blood and into the brain, release of ApoE by astrocytes, and activation of microglia that reduces Aβ plaque pathology and improves cognitive function (Wu et al., 2023).
Alterations in the gut microbiome and involvement of the bidirectional gut-liver-brain axis could be an additional pathway where peripheral antibody treatment can have central effects without antibodies having to penetrate the blood-brain-barrier. The gut microbiome is key in modulating the response of cancer patients to immune activation using checkpoint inhibitor antibodies, for example (for a recent review, see Li et al., 2022).
Delivery of tripartite motif (TRIM) 11, which is reduced in AD brains, into the brain also protects against tau pathology (Zhang et al., 2023). However, TRIM11 promotes tumor progression and high TRIM11 levels are associated with reduced survival of colon cancer patients and increased resistance to chemotherapy (Noble and Hanger, 2023). HSPGs play important roles in cancer initiation and progression and are targets for cancer therapy (Onyeis et al., 2020). ApoE isoforms may also be important in cancer. E4 prolongs survival in melanoma patients, while E2 associates with shorter survival (Ostndorf et al., 2020). APOE genotype also modulates aggressive behavior in prostate cancer cells by modulating cholesterol metabolism (Ifere et al., 2013). Therefore, an important question to address is whether peripherally reducing β-HSPG binding affects cancer risk or tumor progression in addition to reducing tau pathology in the brain.
References:
Saroja SR, Gorbachev K, Julia T, Goate AM, Pereira AC. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2108870119. Epub 2022 Aug 15 PubMed.
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Giannisis A, Patra K, Edlund AK, Nieto LA, Benedicto-Gras J, Moussaud S, de la Rosa A, Twohig D, Bengtsson T, Fu Y, Bu G, Bial G, Foquet L, Hammarstedt C, Strom S, Kannisto K, Raber J, Ellis E, Nielsen HM. Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice. Mol Psychiatry. 2022 Apr 13; PubMed.
Kessler K, Giannisis A, Bial G, Foquet L, Nielsen HM, Raber J. Behavioral and cognitive performance of humanized APOEε3/ε3 liver mice in relation to plasma apolipoprotein E levels. Sci Rep. 2023 Jan 31;13(1):1728. PubMed.
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View all comments by Jacob RaberThis paper provides more evidence that interactions between APOE-HSPG may be involved in AD. Additionally, neurons secrete SPOCK1, which encodes testican1, which is a heparan sulfate and chondroitin sulfate proteoglycan. SPOCK1 is essential in forming and maintaining the blood brain barrier (BBB).
References:
O'Brown NM, Patel NB, Hartmann U, Klein AM, Gu C, Megason SG. The secreted neuronal signal Spock1 promotes blood-brain barrier development. Dev Cell. 2023 Sep 11;58(17):1534-1547.e6. Epub 2023 Jul 11 PubMed.
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