Preman P, Moechars D, Fertan E, Wolfs L, Serneels L, Shah D, Lamote J, Poovathingal S, Snellinx A, Mancuso R, Balusu S, Klenerman D, Arranz AM, Fiers M, De Strooper B. APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia. EMBO Mol Med. 2024 Dec;16(12):3113-3141. Epub 2024 Nov 11 PubMed.

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  1. This paper by Preman and colleagues provides interesting insights into the biology of astrocyte-derived APOE and how it relates to microglial activation and AD plaque pathology. While historical evidence supports APOE4 promoting plaque formation, there is much less known about the APOE2 isoform associated with AD resilience. Clinical studies have shown that individuals with AD carrying an APOE2 allele exhibit reduced amyloid plaque densities and lower terminal Braak scores than APOE3/3 carriers (Bennett et al., 2009; Serrano-Pozo et al., 2015), leading many to believe that APOE2 has an inverse relationship to APOE4, which increases risk for AD up to 15-fold (Strittmatter et al., 1993) .

    Here, the authors present a compelling case that astrocytic APOE2 increases amyloid plaque load to almost the same degree of to that of APOE4, while also increasing soluble Aβ1-42. This is a complex finding that requires future exploration, as increased soluble Aβ typically negatively relates to plaque load, which is observed when astrocytic APOE4 is overexpressed or in APOE-deficient mice. The finding with astrocytic APOE2 suggests a deficit in the feedback mechanisms that regulate secreted Aβ when fibrillar Aβ begins to aggregate in the brain parenchyma. APOE is involved in the endolysosomal system, and alterations of this multi-step process could be a possible mechanism by which APOE2 acts. It would be intriguing for the authors to identify the downstream events that eventually cause AD resilience in APOE2 carriers, as these results suggest that APOE2 in astrocytes exacerbate this process. It would also be interesting to see these findings complemented by a genetic model, such as APOE2/3/4 conditionally driven by an astrocytic promoter, which would also allow for the exploration of interacting APOE isoforms, because APOE2/2 and APOE4/4 carriers are quite rare, and additional pleiotropy may be induced by diverse isoform combinations.
     
    The authors also focused on the non-autonomous impacts of astrocyte-derived APOE2/3/4 on plaque pathology and microglial activation. While there has been a large amount of interest in microglial APOE biology, since up-regulated APOE was defined as a key marker of disease-associated microglia (DAM) (for example, Keren-Shaul et al., 2017) , and microglia-derived APOE4 has been implicated in promoting damaging lipid droplet formation (Haney et al., 2024), few studies have focused on the pleiotropic effects of APOE isoforms derived from astrocytes. The model developed here was appropriate for exploring the non-autonomous impacts of astrocytic APOE isoforms because the surrounding parenchymal cell types are Apoe-deficient. Astrocyte-microglia interactions are thought to be central factors driving early AD neuropathology, so the authors first explored the relationship between astrocyte overexpression of each APOE isoform with microglial dynamics, and similar to the amyloid-based findings they also observed that astrocytic APOE2 and APOE4 caused increased amounts of plaque-associated microglia, without overt changes in microglial morphology. Therefore, they tested the possibility that astrocytic APOE directly modifies microglial responses that eventually sculpt plaques. Using the CSF1R/c-Kit inhibitor PLX3397, they depleted microglia in mice from 2 to 6 months of age and observed that while astrocytic APOE sufficiently deposits plaques, the relationship between APOE levels and soluble Aβ was lost with microglia depleted. This result complements another publication from the same group suggesting that homeostatic microgliaplay a pivotal role in the initial seeding of amyloid plaques in the same APPNL-G-F mouse model used here (Baligács et al., 2024). Therefore, microglia could receive signals from astrocytes to cause plaque accumulation that are altered by APOE isoform, and microglial APOE may act downstream in this process.
     
    This work is very exciting as it brings new insights into APOE biology, and I look forward to seeing where they take the research next, especially with exploring this cascade of interactive events with microglia, astrocytes, and APOE isoforms.

    References:

    Baligács N, Albertini G, Borrie SC, Serneels L, Pridans C, Balusu S, De Strooper B. Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer's Disease. Nat Commun. 2024 Dec 5;15(1):10634. PubMed.

    Bennett DA, De Jager PL, Leurgans SE, Schneider JA. Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles. Neurology. 2009 Apr 28;72(17):1495-503. PubMed.

    Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol. 2015 Jun;77(6):917-29. PubMed.

    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. PubMed.

    View all comments by Sarah Heuer

  2. This study adds important mechanistic insight into how astrocyte expression of different APOE isoforms can contribute to AD pathology. It is intriguing that amyloid levels in APPNL-G-F mice with APOE2 were elevated compared to APOE3. A previous study had similarly found that insoluble Aβ42 was higher in APPNL-G-F mice that expressed APOE2 than APOE3 at 6 months of age (Holden et al., 2022). Interestingly, Holden et al. did not observe similar elevations in insoluble Aβ42 in APOE2-expressing APPNL-G-F mice at 18 months of age, a model that exhibits a much delayed, milder overall amyloid phenotype. These observations were consistent with previous work showing reduced amyloid deposition in APOE2-expressing models such as PDAPP (Fagan et al., 2002).

    The mechanism underlying these curious APOE2-related amyloid effects in different models is unclear, but it may relate to how aggressive the amyloid model is, either due to the relative amount of Aβ42 and Aβ40 produced or the amyloidogenic nature and different sequence of the Aβ species itself in the case of the APPNL-G-F mouse. It may also, as the authors mention, point to non-amyloid-dependent effects of APOE2 on pathological events downstream of amyloid, such as inflammation or tau pathology.

    References:

    Holden S, Kundu P, Torres ER, Sudhakar R, Krenik D, Grygoryev D, Turker MS, Raber J. Apolipoprotein E Isoform-Dependent Effects on Human Amyloid Precursor Protein/Aβ-Induced Behavioral Alterations and Cognitive Impairments and Insoluble Cortical Aβ42 Levels. Front Aging Neurosci. 2022;14:767558. Epub 2022 Mar 1 PubMed.

    Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis. 2002 Apr;9(3):305-18. PubMed.

    View all comments by Jason Ulrich View all comments by David Holtzman

  3. It is well established that APOE isoforms differently modulate amyloid pathology, and that APOE4 leads to significant increases in amyloid plaque burden in Alzheimer’s disease (Huynh et al., 2017; Raulin et al., 2022; Koutsodendris et al., 2022). However, APOE is produced by various cell types within the brain, and work done by our lab and others has found that APOE derived from astrocytes (Wang et al., 2021), neurons (Koutsodendris et al., 2023), and microglia (Yin et al., 2023) all exert different pathological effects on AD-related pathologies. Here, Preman and colleagues performed an impressive and rigorous study to address outstanding questions in the field surrounding the roles of the different APOE isoforms derived from astrocytes in amyloid plaque formation and microglial reactivity.

    To study this, APOE isoforms were packaged into a recombinant AAV2/8 vector and driven under an astrocyte-specific promoter, ALDH1L1. These viral particles were injected  intracerebroventricularly to induce the expression of one of three APOE isoforms in astrocytes of mice that lack endogenous mouse APOE and express human mutant APP at endogenous levels (APPNL-G-F X APOE- / - ).

    The main findings confirm that astrocytic APOE4 promotes fibrillar amyloid plaque formation in this mouse model. Astrocytic APOE4 expression also induced microglial reactivity and upregulation of disease-associated-microglia (DAM) transcriptional markers. This suggests that astrocytic APOE4 plays a key role in promoting amyloid plaque formation and microgliosis. Still, depletion of microglia using PLX3397, in the presence of astrocytic APOE4, led to a significant decrease in amyloid plaque burden, suggesting that microglia are independent modulators of amyloid formation and act congruently with astrocytic APOE4 to further promote this pathology.

    Interestingly, this study found that expression of APOE2 in astrocytes led to increased amyloid plaque formation compared to APOE3. The authors suggest that the protective roles of APOE2 are likely downstream of amyloid pathology in AD. While it’s possible this is the case, APOE2 is generally considered to be protective against the formation of AD pathologies (Li et al., 2020) and several studies indicate that APOE2 decreases amyloid burden (Castellano et al., 2011; Fagan et al., 2002; Hudry et al., 2013; Zhao et al., 2016). Another possibility is that the cellular source of APOE2 plays a critical role in its protective effects and that alternative cellular sources of APOE2, such as neuronal APOE2, may exert stronger protective effects against amyloid burden than astrocytic APOE2. We previously reported that neuronal APOE4 is an important driver of tau pathology and gliosis (Koutsodendris et al., 2023), so it would be interesting to perform follow-up studies using a similar model to investigate the roles of different neuronal APOE isoforms in amyloid plaque formation.

    References:

    Huynh TV, Davis AA, Ulrich JD, Holtzman DM. Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res. 2017 May;58(5):824-836. Epub 2017 Feb 27 PubMed.

    Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022 Nov 8;17(1):72. PubMed.

    Koutsodendris N, Nelson MR, Rao A, Huang Y. Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annu Rev Pathol. 2022 Jan 24;17:73-99. Epub 2021 Aug 30 PubMed.

    Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.

    Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, Yip O, Rao A, Nelson MR, Hao Y, Thomas R, Yoon SY, Arriola P, Huang Y. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 2023 Nature Aging

    Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry JL, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJ, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. Nat Immunol. 2023 Nov;24(11):1839-1853. Epub 2023 Sep 25 PubMed.

    Li Z, Shue F, Zhao N, Shinohara M, Bu G. APOE2: protective mechanism and therapeutic implications for Alzheimer's disease. Mol Neurodegener. 2020 Nov 4;15(1):63. PubMed.

    Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57. PubMed.

    Fagan AM, Watson M, Parsadanian M, Bales KR, Paul SM, Holtzman DM. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis. 2002 Apr;9(3):305-18. PubMed.

    Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM, Hashimoto T, Scheel M, Spires-Jones T, Arbel-Ornath M, Betensky R, Davidson BL, Hyman BT. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med. 2013 Nov 20;5(212):212ra161. PubMed.

    Zhao L, Gottesdiener AJ, Parmar M, Li M, Kaminsky SM, Chiuchiolo MJ, Sondhi D, Sullivan PM, Holtzman DM, Crystal RG, Paul SM. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging. 2016 Aug;44:159-72. Epub 2016 Apr 30 PubMed.

    View all comments by Nicole Koutsodendris View all comments by Yadong Huang

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Mutations

  1. APOE C130R (ApoE4)
  2. APOE R176C (ApoE2)