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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.
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National Institutes of Health
Variants of APOE have been known for years to influence disease risk and progression. However, teasing apart the cell types that are important to APOE’s effects has remained a challenge. Papers using iPSC-derived cell types in monoculture, co-culture, and complex multicellular cultures have tried to tackle this challenge and have made some key discoveries about cellular effects of APOE alleles; APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia (Lin et al., 2018; Sienski et al., 2021; Narayan et al., 2020; Victor et al., 2022; Koutsodendris et al., 2023; Blanchard et al., 2020; Blanchard et al., 2022) however, the broader tissue, pathological, and organismal effects remain elusive. Moreover, it is unlikely that cells in an incubator will capture all the nuances of the mouse brain environment. This is especially important for cells that sense, and adapt to, their environment constantly, such as microglia. These twin papers both explore the role of microglial APOE isoforms in the context of neurodegenerative disease models of amyloid disease and tauopathy.
The two papers take different approaches, each providing their own insights. Liu and Wang et al. use a microglial-specific knock-in of the human APOE3 or APOE4 alleles in the context of an APOE-/- background, whereas Yin and Rosenzweig et al. specifically deleted only microglial APOE in the context of the humanized knock-in APOE mouse model.
Both papers demonstrate conclusively that microglial APOE does contribute to pathology. Both papers acknowledge the involvement of other cell types as well, with special focus on the interplay between astrocytes and microglia (in Yin and Rosenzweig et al.). Both papers perform extensive transcriptomic characterization to show that APOE isoforms alter the transcriptional state(s) of microglia.
From my perspective, it was a nice reinforcement of our initial observation in iPSC culture (Sienski et al., 2021), as well as that of others (Victor et al., 2022; Blanchard et al., 2022; Haney et al., 2023).
to see that in so many different mouse systems, APOE4 correlates with lipid droplet accumulation in microglia! Additionally, as a member of the iNDI team, it is heartening to see Liu and Wang et al. utilize microglia derived from the iNDI isogenic APOE lines to support findings from their mouse studies (see May 2021 news on iNDI).
The differences in mouse models led to some intriguing observations. Liu and Wang et al. noted slightly different effects of APOE3 and APOE4 when expressed in an APOE-/- versus a background with murine ApoE. This draws attention to the fact that murine ApoE changes the role of human APOE expression in a variant-specific manner. Yin and Rosenzweig et al. noted sex differences in their outcomes, suggesting that microglial responses, especially APOE-dependent ones, may be influenced by sex of the organism.
Microglial APOE has a role to play in disease pathology, and APOE4 is worse for pathology than APOE3. Both studies show us microglia are important, but other cell types are, too. The interplay of these cell types, the APOE genotype, and environmental factors may initiate or exacerbate progression of AD.
References:
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