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.
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:
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH.
APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.
Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31
PubMed.
Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, Ralvenius WT, Akay L, Lockshin E, He L, Milo B, Graziosi A, Baru V, Lewis CA, Kellis M, Sabatini DM, Tsai LH, Lindquist S.
APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia.
Sci Transl Med. 2021 Mar 3;13(583)
PubMed.
Narayan P, Sienski G, Bonner JM, Lin YT, Seo J, Baru V, Haque A, Milo B, Akay LA, Graziosi A, Freyzon Y, Landgraf D, Hesse WR, Valastyan J, Barrasa MI, Tsai LH, Lindquist S.
PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4.
Cell Rep. 2020 Oct 6;33(1):108224.
PubMed.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH.
Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity.
Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8.
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 Mar;3(3):275-296. Epub 2023 Feb 20
PubMed.
Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, Victor MB, Bonner JM, Mathys H, Lin YT, Ko T, Bennett DA, Cam HP, Kellis M, Tsai LH.
Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes.
Nat Med. 2020 Jun;26(6):952-963. Epub 2020 Jun 8
PubMed.
Correction.
Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R'Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH.
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
Nature. 2022 Nov;611(7937):769-779. Epub 2022 Nov 16
PubMed.
Farmer BC, Kluemper J, Johnson LA.
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation.
Cells. 2019 Feb 20;8(2)
PubMed.
Haney MS, Pálovics R, Munson CN, Long C, Johansson P, 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 microglia.
bioRxiv. 2023 Jul 25;
PubMed.
Comments
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:
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.
Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, Ralvenius WT, Akay L, Lockshin E, He L, Milo B, Graziosi A, Baru V, Lewis CA, Kellis M, Sabatini DM, Tsai LH, Lindquist S. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021 Mar 3;13(583) PubMed.
Narayan P, Sienski G, Bonner JM, Lin YT, Seo J, Baru V, Haque A, Milo B, Akay LA, Graziosi A, Freyzon Y, Landgraf D, Hesse WR, Valastyan J, Barrasa MI, Tsai LH, Lindquist S. PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4. Cell Rep. 2020 Oct 6;33(1):108224. PubMed.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. 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 Mar;3(3):275-296. Epub 2023 Feb 20 PubMed.
Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, Victor MB, Bonner JM, Mathys H, Lin YT, Ko T, Bennett DA, Cam HP, Kellis M, Tsai LH. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med. 2020 Jun;26(6):952-963. Epub 2020 Jun 8 PubMed. Correction.
Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R'Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022 Nov;611(7937):769-779. Epub 2022 Nov 16 PubMed.
Farmer BC, Kluemper J, Johnson LA. Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation. Cells. 2019 Feb 20;8(2) PubMed.
Haney MS, Pálovics R, Munson CN, Long C, Johansson P, 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 microglia. bioRxiv. 2023 Jul 25; PubMed.
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