17 Dec 2023

The astonishing case of Aliria Rosa Piedrahita de Villegas captivated scientists because she was spared the wrath of her Paisa presenilin 1 mutation. She staved off dementia for three decades longer than her kin and had few neurofibrillary tangles, mild hippocampal neurodegeneration, and minimal neuroinflammation despite a high amyloid plaque load (Sep 2022 conference news). Piedrahita de Villegas carried two copies of a rare APOE3 variant called Christchurch. Was this really to thank for her delayed symptoms and eased pathology? Two new papers suggest as much.

In mice, APOE3-Christchurch reduced amyloidosis, tauopathy, and tau spreading.
Two copies of APOE4-Christchurch staved off tangles, gliosis, and neurodegeneration.
Just one copy reduced gliosis and atrophy but not tauopathy.

In the December 11 Cell, scientists led by David Holtzman at Washington University in St. Louis described remarkably similar effects of APOE3-Christchurch in amyloidosis mice injected with tau fibrils. They had fewer plaques and tangles than their E3 counterparts and little tau spreading.

Yadong Huang and colleagues at the University of California, San Francisco, saw that the Christchurch variant can also protect against pathology driven by ApoE4. In the November 13 Nature Neuroscience, they reported that replacing two copies of the mouse gene with APOE4-Christchurch prevented tau accumulation, gliosis, and atrophy in tauopathy mice. Swapping one copy reduced gliosis and neurodegeneration, but not tauopathy.

“A definitive link of the APOE variant to the phenotype did not exist until [these publications],” Kenneth Kosik of the University of California, Santa Barbara, wrote. Joseph Arboleda-Velasquez of Massachusetts Eye and Ear in Boston, who co-authored Huang’s paper, noted that human case reports offer insight into disease pathology that animal experiments can tease out further. “[These papers] compellingly present evidence of the robust and multifaceted protective effects of APOE Christchurch,” he wrote (comments below).

To explore the effect of the APOE Christchurch variant on AD pathology, first author Yun Chen in Holtzman's lab crossed the APP/PS1 model of amyloidosis with APOE3 knock-ins or mice expressing two copies of APOE3 with the R136S point mutation, aka Christchurch. By six months of age, APP/PS1 mice have rampant plaques, so Chen injected tau fibrils isolated from human AD tissue into the cortices and hippocampi of APOE/amyloidosis animals at that age, then assessed pathology at 9.5 months.

APOE3-Christchurch mice had 40 percent fewer amyloid plaques than their E3 counterparts. Using high-power confocal microscopy, the scientists homed in on changes around plaques. There, they saw more synapsin and PSD95, markers of pre- and post-synapses, respectively, in the Christchurch mice. Fewer AT8-positive tau puncta and less β-secretase 1 (BACE1) surrounded plaques, a sign of fewer dystrophic neurites (image below). More microglia swarmed plaques, and they highly expressed the phagocytic marker CD68, hinting they might be mopping up errant proteins. This suggests that APOE3-Christchurch reduces amyloid and tau accumulation, causing less damage to nearby neurons.

More Neurons, Less Pathology. Around amyloid plaques (blue) in APPPS1/APOE3 mice (left two columns), neurons withered (green, top row), p-tau accumulated (green, middle row), and dystrophic neurites ballooned (yellow, bottom row). In mice with the Christchurch variant (right two columns), more neurons survived and there was less pathology. [Courtesy of Chen et al., Cell, 2023.]

The Christchurch mutation also curbed the propagation of tau pathology from seeds injected into the hippocampus and cortex. From there, fibrils spread throughout those brain areas in the APOE3 mice, as seen by AT8 immunohistochemistry. In contrast, the fibrils stayed where the scientists injected them in the Christchurch mice. What stopped the spreading? Cultured bone marrow-derived macrophages from wild-type mice expressing APOE3-Christchurch phagocytosed more tau fibrils, and secreted fewer fluorescent tau seeds, than did APOE3-expressing macrophages. The researchers believe microglia, which are harder to isolate in large quantities, probably behave similarly. “APOE3-Christchurch likely increases microglial uptake and degradation of tau better than do other isoforms,” Holtzman concluded.

Why did this variant boost the macrophages' appetite? Tau and APOE both bind cell-surface heparan sulfate proteoglycans (HSPGs). Tau fibrils piggyback on these sticky molecules to penetrate cells, but the Christchurch mutation, which lies in the HSPG binding domain, weakens the APOE-HSPG interaction (May 2018 news; Nov 2019 news). The scientists suspected that this leaves more HSPG molecules free to latch onto tau, allowing more fibrils to enter microglia.

Indeed, adding recombinant ApoE3-Christchurch protein to cultured macrophages did not slow the uptake of added tau fibrils, but recombinant ApoE3 did. “[These] findings reveal involvement of microglia in the mechanisms of protection, a facet not evident in previous analyses,” wrote Arboleda-Velasquez, who is developing an antibody to mimic Christchurch by weakening HSPG binding to APOE (Oct 2023 news).

What About APOE4?
For his part, Huang was curious if the Christchurch mutation counters ApoE4 effects on pathology. First author Maxine Nelson crossed P301S tauopathy mice with human APOE3 knock-in mice, with E4 knock-ins, or with E4 knock-ins expressing one or two copies of Christchurch. Because the P301S mice develop gliosis, neurofibrillary tangles, and neurodegeneration by 10 months of age, Nelson analyzed those pathologies in offspring at that age.

APOE4-Christchurch tempered micro- and astrogliosis. These were rampant in the hippocampi of P301S/APOE4 animals, but heterozygous Christchurch mice had but one-quarter as many Iba1-positive microglia and GFAP-positive astrocytes, 10-fold fewer disease-associated microglia (DAMs), and half as many disease-associated astrocytes (DAAs). Christchurch homozygotes had almost no DAMs or DAAs and even less gliosis than heterozygotes—about as much as in P301S/APOE3 knock-ins (image below). Notably, Holtzman also saw less overall microgliosis in homozygous APOE3-Christchurch mice, likely a reflection of having fewer plaques.

Calmed by Christchurch. Compared to P301S/APOE4 mice (left column), APOE4-Christchurch heterozygotes (second column) had less astro- (top row) and microgliosis (bottom row). The Christchurch homozygotes (third column) had even less gliosis, about as much as P301S/APOE3 animals (right column). [Courtesy of Nelson et al., Nature Neuroscience, 2023.]

This gene dosage trend held for neurodegeneration. One APOE4-Christchurch allele halved hippocampal and dentate gyrus atrophy compared to P301S/APOE4 animals, while two copies slowed it to that of P301S/APOE3 mice (image below). Christchurch homozygotes and, to a lesser extent, heterozygotes, had more excitatory neurons and upregulated genes related to neuron health, such as axon guidance, synaptic integrity, and long-term potentiation, suggesting that Christchurch protected against neuron loss.

Opposing Effects. While neurons (white) in the dentate gyrus degenerated (left column) and p-tau aggregated (brown, right column) in P301S/APOE4 mice (top row), animals with one copy of Christchurch (second row) had no neurodegeneration but did have tauopathy. Two copies of the APOE variant protected mice from both pathologies (third row) almost as well as did the APOE3 isoform (bottom row). [Courtesy of Nelson et al., Nature Neuroscience, 2023.]

Tau pathology bucked the trend. Heterozygous APOE4-Christchurch mice had as much AT8-positive p-tau202/205 as their P301S/APOE4 counterparts, and tangles spread throughout their entire hippocampi. In contrast, Christchurch homozygotes had half as many tangles, and they were limited to the CA3 area of the hippocampus, roughly the amount and distribution seen in P301S/APOE3 mice (image above). Why did one copy of APOE4-Christchurch stave off atrophy but not tauopathy?

Huang suspected a difference in tau uptake by neurons. He tested this theory using human iPSC-derived neurons engineered to express one or two copies of APOE4-Christchurch. Heterozygous cells engulfed as much fluorescently labeled recombinant tau, and had as many p-tau202/205 aggregates, as did APOE4 neurons. Yet homozygous cells took up half as much labeled tau and contained 40 percent less p-tau. To Huang, this implies that the negative effects of two APOE4 alleles outweigh the protection by a Christchurch variant, allowing tau to invade and damage heterozygous neurons.

The partial protection in heterozygous mice aligns with epidemiological evidence that heterozygous APOE3-Christchurch/Paisa carriers had delayed cognitive symptoms for a few years past their expected age of onset (Aug 2023 conference news). Because Christchurch seems to protect against APOE3 and E4 alleles similarly, Huang believes reduced gliosis and atrophy explains this delay.

Other explanations were sought by scientists who studied 37 Christchurch heterozygotes among 455,000 U.K. Biobank participants (He et al., 2023). All the heterozygotes carried at least one APOE3 allele, with five having an APOE4 allele and one having the protective APOE2. None had been diagnosed with mild cognitive impairment or AD, though some were as old as 82. Among a plethora of neurological and biological traits, only a low concentration of plasma Apolipoprotein B distinguished the Christchurch carriers from the controls. High levels of ApoB are associated with AD, suggesting that Christchurch might also protect by keeping levels of this other apolipoprotein down.—Chelsea Weidman Burke

Comments

- Kenneth Kosik
  University of California, Santa Barbara
- Posted: 17 Dec 2023
In 2019, Arboleda-Velasquez et al. reported the remarkable case of a woman who harbored the highly penetrant PSEN1-E280A Alzheimer’s mutation, but was spared the disease for 28 years beyond the mean age of onset that occurred in the late 40s of the other family members within this very large kindred. The first notable feature in her evaluation came from brain imaging, which revealed extensive amyloid throughout her brain but quite limited tau pathology. This decoupling of amyloid deposition and tau pathology coincident with being spared from clinical dementia was confirmed when she came to autopsy (Sepulveda-Falla, et al., 2022). As predicted by the live-imaging studies, her brain was filled with amyloid plaques, but tau tangles were confined to the occipital cortex, a very unusual distribution. These observations suggested that the mechanism by which she was spared tau pathology was very likely related to inhibition of tau spread. In the Arboleda-Velasquez lab the search was on for a genetic explanation of her condition. They found an unusual variant in APOE (APOE3-R136S) first reported in Christchurch New Zealand and named for that city where any connection to Alzheimer’s disease was not even suspected.

The original report made the case that APOE3-R136S was linked to this unusual phenotype, but it was widely acknowledged that the hypothesized link needed substantiation. Afterall, it was only one case, and it seemed that the expression of the clinical phenotype required APOE3-R136S homozygosity as observed in this subject. No other family member was known with APOE3-R136S homozygosity, but APOE3-R136S heterozygotes were known. One would like to see gene dosage effects to substantiate a claim of causation. Although the original cohort of APOE3-R136S carriers in the family did not show a delayed onset, a more recent re-evaluation of these cases and the discovery of additional heterozygotes suggested a modest delay in disease onset (personal communication, Arboleda-Velasquez). However, a more definitive link of the APOE variant to the phenotype did not exist until the publication of Nelson et al.

In this elegant study, Nelson and colleagues asked whether APOE3-R136S is protective against APOE4-driven deleterious effects observed in late-onset Alzheimer’s disease. They used a tauopathy mouse model and human iPSC-derived neurons carrying either homozygous or heterozygous APOE4-R136S in contrast to the proband patient, whose background genotype was APOE3. In these experiments, homozygosity protected against tau pathology and neuroinflammation, whereas heterozygosity only protected against the neuroinflammation.

With greater confidence in the original observation concerning APOE3-R136S protection, the next steps require an understanding of the mechanism with a focus on how tau spread might occur. We and others have implicated HSPGs in tau spread (Rauch et al., 2018); however, most studies of tau spread do not address the physico-chemical state of the prion-like tau moiety that spreads. Hence, a better understanding of the precise uptake mechanism utilized for different tau structures that template misfolding in recipient cells is needed, whether uptake occurs through LRP1 (Rauch et al., 2020) or macropinocytosis (Diamond, 2023) or some other mechanism. Interestingly, many of the implicated molecules form a potential disease nexus that includes tau, HSPGs, LRP1, APOE, and amyloid, where interventions might be pinpointed.

An open question is in which cell type the components of this complex operate. Nelson et al. raised some provocative effects of APOE3-R136S on protective astrocyte pools. A second paper by the Holtzman group nicely demonstrated the protective effects of APOE3-R136S. It located the functional significance of the variant on microglia using a humanized knock-in mouse expressing human APOE3-R136S crossed with an Aβ-depositing model (Chen et al., 2023). Insoluble tau fibrils derived from human AD brain extract were injected to assess Aβ-induced tau seeding and spreading. One surprise was that APOE3ch reduced overall amyloid plaque deposition as well as reducing peri-amyloid plaque tau seeding and spreading. Importantly, myeloid cell phagocytosis and degradation of human tau fibrils were enhanced in the presence of APOE3-R136S and was linked to reduced binding of APOE3-R136S to HSPG and LRP1 in vitro. Apparently, the relatively reduced binding of APOE3-R136S permitted increased uptake and degradation of tau fibrils in microglia.

Finally, the extraordinary serendipity of this APOE protective variant deserves mention. Outside of the context of this very large PSEN1 E280A family, it is difficult to imagine that the variant would have been detected, particularly in the homozygous state. Unsurprisingly, this variant was not detected in a recent GWAS study (Cochran et al., 2023), and the distinct coalescent paths through which second variants enter families with rare large effect-size single gene mutations make GWAS detection of protective variants challenging. Nevertheless, the value of these large families for discovery is indisputable, and strategies for finding such protective variants should be developed (Kosik, 2023).

References:

Sepulveda-Falla D, Sanchez JS, Almeida MC, Boassa D, Acosta-Uribe J, Vila-Castelar C, Ramirez-Gomez L, Baena A, Aguillon D, Villalba-Moreno ND, Littau JL, Villegas A, Beach TG, White CL 3rd, Ellisman M, Krasemann S, Glatzel M, Johnson KA, Sperling RA, Reiman EM, Arboleda-Velasquez JF, Kosik KS, Lopera F, Quiroz YT. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 Sep;144(3):589-601. Epub 2022 Jul 15 PubMed.

Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec;26(12):2104-2121. Epub 2023 Nov 13 PubMed.

Rauch JN, Chen JJ, Sorum AW, Miller GM, Sharf T, See SK, Hsieh-Wilson LC, Kampmann M, Kosik KS. Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep. 2018 Apr 23;8(1):6382. PubMed.

Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, Gradinaru V, Kampmann M, Kosik KS. LRP1 is a master regulator of tau uptake and spread. Nature. 2020 Apr;580(7803):381-385. PubMed.

Diamond MI. Travels with tau prions. Cytoskeleton (Hoboken). 2024 Jan;81(1):83-88. Epub 2023 Nov 11 PubMed.

Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.

Cochran JN, Acosta-Uribe J, Esposito BT, Madrigal L, Aguillón D, Giraldo MM, Taylor JW, Bradley J, Fulton-Howard B, Andrews SJ, Acosta-Baena N, Alzate D, Garcia GP, Piedrahita F, Lopez HE, Anderson AG, Rodriguez-Nunez I, Roberts K, Dominantly Inherited Alzheimer Network, Absher D, Myers RM, Beecham GW, Reitz C, Rizzardi LF, Fernandez MV, Goate AM, Cruchaga C, Renton AE, Lopera F, Kosik KS. Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimers Dement. 2023 Sep;19(9):3835-3847. Epub 2023 Mar 23 PubMed.

Kosik KS. Search Strategies for Alzheimer Protector Genes. Ann Neurol. 2023 Oct;94(4):613-617. Epub 2023 Aug 26 PubMed.

View all comments by Kenneth Kosik

- Joseph Arboleda-Velasquez
  Schepens Eye Research Institute and Harvard Medical School
- Posted: 17 Dec 2023
As demonstrated by our original APOE Christchurch publication (Arboleda-Velasquez et al., 2019), case reports can be exceptionally sensitive in uncovering new mechanisms, offering unique insights into biology, pathophysiology, and, in this instance, resistance within the context of a “genetics of health” paradigm.

We should acknowledge the wealth of information that can emerge from n=1 studies. While there is a substantial need for extensive research to sway skeptics, these papers compellingly present evidence of the robust and multifaceted protective effects of APOE-Ch. It is worth noting the challenging path the original case report faced during peer review elsewhere before its eventual publication in Nature Medicine. At the time, it appeared that some reviewers were reluctant to disseminate these findings widely. Reflecting on this in hindsight, it is clear that the Christchurch case could have emerged in 2017 already.

Discovering a protective effect, especially one with such significant impact leading to complete rescue, is both thrilling and humbling. It raises the question of whether the field should have pursued APOE as a therapeutic target in earnest much earlier. Compared to amyloid and tau, APOE has received less attention for therapeutics. To those considering our finding unexpected, the protective effects of APOE2 reported decades ago could have served as a notice.

Our original report showcased protection in the context of the severe E280A PSEN1 mutation in an APOE3/3 background. Therefore, Nelson et al. demonstrating robust protection of Christchurch in APOE4/E4 mice is highly encouraging, suggesting broad effects with potential implications for millions of APOE4 carriers at risk of or already affected by Alzheimer's.

The work by Chen et al. delves into the impact of ApoECh on amyloid-related pathology, shedding light on an aspect of the original report that has been somewhat overlooked—the influence on amyloid. PET imaging of the case revealed extensive amyloid pathology, while the presence of tauopathy was lower than anticipated. Despite this, we conducted investigations into the potential impact of ApoECh on amyloid fibrillation and oligomerization, findings originally included in our report. These results, though somewhat divergent from the main narrative, have now undergone independent validation, reaffirming their significance.

Regarding the therapeutic potential of mimicking the Christchurch mutation, Nelson et al.'s results emphasize that APOE Christchurch can safeguard mice even when present in only one copy, highlighting the potential effectiveness of APOE-Ch based therapeutics. Chen et al.'s results suggest that ApoE-Ch's efficacy might stem from its influence on multiple mechanisms encompassing both amyloid and tau pathologies, not just from a single process. Instead, the protection could be the culmination of various effects on ApoE, pivotal in numerous stages of the condition. ApoE Christchurch's potency could be attributed to its dual impact, serving as a formidable combination in combating Alzheimer's.

Marino and Perez et al. recently unveiled antibodies that emulate the impact of ApoE Christchurch. Their preclinical studies demonstrated efficacy in tauopathy models. The recent paper from the Holtzman group underscores the necessity of exploring the antibody's performance in amyloid models, highlighting a pivotal next step in understanding its broader therapeutic potential.

The two recent papers shed light on the significance of diminished ApoE Christchurch interactions with heparan sulfate proteoglycans, a crucial element in its protective effect against Alzheimer's. While this concept was proposed in the original report, this new work supplies experimental evidence validating it. Moreover, Chen et al.'s findings implicate microglia in the mechanisms of protection, a facet not evident in previous analyses.

References:

Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA, Leyton-Cifuentes D, Chen K, Baena A, Aguillon D, Rios-Romenets S, Giraldo M, Guzmán-Vélez E, Norton DJ, Pardilla-Delgado E, Artola A, Sanchez JS, Acosta-Uribe J, Lalli M, Kosik KS, Huentelman MJ, Zetterberg H, Blennow K, Reiman RA, Luo J, Chen Y, Thiyyagura P, Su Y, Jun GR, Naymik M, Gai X, Bootwalla M, Ji J, Shen L, Miller JB, Kim LA, Tariot PN, Johnson KA, Reiman EM, Quiroz YT. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.

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.

View all comments by Joseph Arboleda-Velasquez

- David Holtzman
  Washington University
- Posted: 17 Dec 2023
- Paper: The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.
In 2019, a rare variant on an APOE3 background (APOE3-R136S), Christchurch mutation, when present in the homozygous state, was found to be associated with a marked delay in cognitive decline in an individual with the PSEN1-E280A mutation that causes autosomal-dominant AD. Whether this variant is responsible for this protection was not clear. This individual did not develop cognitive decline until around age 70, a 25-year delay relative to others with this PSEN1 mutation. Interestingly, this individual, like others with the PSEN1-E280 mutation, had substantial amyloid deposition in the brain. However, the amount of tau pathology was much less than is seen in others with this mutation and the distribution was altered compared to the normal pattern. As there is a lot of data suggesting that in AD, amyloid both exacerbates and leads to spreading and progression of tau pathology, it appeared that if the APOE3ch variant was the cause for protection, it somehow attenuated the effect of amyloid on tau.

In this new paper by Nelson et al. from the lab of Yadong Huang, the group asked if the Christchurch mutation when put onto an APOE4 backbone, would influence tauopathy of tau-mediated neurodegeneration using both the PS19 mouse model of tauopathy as well as in human iPSC induced neurons. Interestingly, in the PS19 model, they found that compared to APOE4, APOE4ch resulted in reduced p-tau accumulation as well as strongly reduced tau-mediated neurodegeneration. The neurodegeneration was also partially reduced in mice heterozygous for E4ch. The decrease in p-tau and neurodegeneration in the presence of E4ch was also linked with decreased reactive astrocytes and microglia. It seems clear from this well-performed study that, even when on an APOE4 background, the R136S variant results in a protection against tauopathy and tau-mediated neurodegeneration.

There are several possible mechanisms that might lead to this neuroprotective effect. The one explored in this paper is whether APOE4ch might be inhibiting tau uptake or in some way preventing against p-tau accumulation. By using iPSC induced neurons that were E4, E4ch, E3, or EKO, they present data showing that monomeric tau uptake is strongly decreased by HSPG and that E4ch reduces monomeric tau uptake, likely due to its decrease in HSPG binding. They also showed that over several days, E3ch reduced endogenous p-tau levels compared to E4 neurons and that the effect seen in E4 neurons was inhibited with HSPG treatment.

These experiments are interesting and well done. A number of papers have shown in mouse models that APOE and APOE variants can influence tauopathy and tau-mediated neurodegeneration. Whether the mechanisms leading to this effect in vivo involve the effect of APOE or APOE variants directly on neurons, as is suggested by these experiments, or they involve other mechanisms such as effects of APOE on cells such as microglia, which is suggested by other work, is not yet clear. The importance of the current work is that this shows that the R136S variant, even when on the APOE4 backbone, protects against tauopathy and tau-mediated neurodegeneration. It also provides one potential mechanism to follow up on regarding this strong neuroprotective effect of the variant, and suggests that this APOE-HSPG binding site is a target to further explore as a therapeutic target.

View all comments by David Holtzman

- Dena Dubal
  University of California, San Francisco
- Posted: 17 Dec 2023
Protective missense variants in APOE—or those that change an amino acid in the protein sequence of APOE—are very rare. Nonetheless, they are incredibly important because understanding how they nearly abrogate an increased risk of AD may pave the way to new therapeutics against the devastating disease. This is why both Nelson et al. and Chen et al.—who probe protective mechanisms of the Christchurch variant—are exciting and impactful as we imagine new APOE-directed therapies for AD.

Nelson et al., 2023, found that homozygous insertion of the R136S variant into APOE4 rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Using the PS19 mouse tauopathy model alongside human iPSC-derived neurons strengthened their data, since both models showed convergent findings. It’s remarkable that insertion of the R136S variant into APOE4 decreased APOE4-linked neuronal uptake of tau, possibly through decreasing heparin binding. Could this, in part, explain why the individual who was a homozygous carrier of the E3-Christchurch variant showed minimal tau burden and was resistant to autosomal-dominant AD?

The data inspire us toward specific modifications that may target heparin binding by APOE to protect against AD. Would this afforded protection need to be specific to APOE4-induced pathology? Maybe not, as the R136S variant was originally observed in the APOE3 gene. Perhaps its protective reach on tau is even further and broader than APOE4.

Indeed, Chen et al., 2023, used a humanized knock-in of APOE3 with and without the Christchurch variant, in the absence and presence of an Aβ-depositing model (APP/PS1 mice). They studied how injected tau seeded and spread through mice brains with or without amyloid. They found that E3-Christchurch reduced plaque-associated tau pathology. In vitro they show that myeloid cells (precursors to microglia) expressing E3-Christchurch showed more tau fibril uptake and less of its release, suggesting that microglia might degrade more tau and also keep it from spreading.

It’s particularly exciting that this study identifies and delineates an interaction between Aβ and tau—with Aβ either amplifying or enabling the E3-Christchurch-mediated protective effects on tau. This reminds us of the individual homozygous for E3-Christchurch carrying a gene for autosomal-dominant AD who had heavy amyloid but very little tau burden in her brain. How might Aβ “prime” the brain to facilitate a protective effect of the E3-Christchurch variant against tau?

Both studies are important, well-executed, and provide deeper mechanistic insight into the E3-Christchurch variant. Future studies probing the role of E3-Christchurch on cognition and its substrates will be particularly illuminating. The protected individual with the E3-Christchurch variant had mild cognitive deficits despite carrying an autosomal-dominant AD mutation. Did the E3-Christchurch mutation directly or indirectly modify systems and circuits underlying learning and memory—leading to minimal clinical deficits?

View all comments by Dena Dubal

APOE Christchurch Variant Tames Tangles and Gliosis in Mice

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