Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

Matheus B. Victor; Noelle Leary; Xochitl Luna; Hiruy S. Meharena; Aine Ni Scannail; P. Lorenzo Bozzelli; George Samaan; Mitchell H. Murdock; Djuna von Maydell; Audrey H. Effenberger; Oyku Cerit; Hsin Lan Wen; Liwang Liu; Gwyneth Welch; Maeve Bonner; Li Huei Tsai

doi:10.1016/j.stem.2022.07.005

Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

Matheus B. Victor, Noelle Leary, Xochitl Luna, Hiruy S. Meharena, Aine Ni Scannail, P. Lorenzo Bozzelli, George Samaan, Mitchell H. Murdock, Djuna von Maydell, Audrey H. Effenberger, Oyku Cerit, Hsin Lan Wen, Liwang Liu, Gwyneth Welch, Maeve Bonner, Li Huei Tsai

Research output: Contribution to journal › Article › peer-review

162 Scopus citations

Abstract

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

Original language	English
Pages (from-to)	1197-1212.e8
Journal	Cell Stem Cell
Volume	29
Issue number	8
DOIs	https://doi.org/10.1016/j.stem.2022.07.005
State	Published - 4 Aug 2022
Externally published	Yes

Keywords

APOE
Alzheimer's risk variant
GIRKs
calcium dynamics
forebrain spheroids
lipid droplet
microglia
network-activity
stem cells

Access to Document

10.1016/j.stem.2022.07.005

Cite this

Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., Cerit, O., Wen, H. L., Liu, L., Welch, G., Bonner, M., & Tsai, L. H. (2022). Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell, 29(8), 1197-1212.e8. https://doi.org/10.1016/j.stem.2022.07.005

@article{6f19effc072745a69f9082271f6b2e1b,

title = "Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity",

abstract = "Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.",

keywords = "APOE, Alzheimer's risk variant, GIRKs, calcium dynamics, forebrain spheroids, lipid droplet, microglia, network-activity, stem cells",

author = "Victor, \{Matheus B.\} and Noelle Leary and Xochitl Luna and Meharena, \{Hiruy S.\} and Scannail, \{Aine Ni\} and Bozzelli, \{P. Lorenzo\} and George Samaan and Murdock, \{Mitchell H.\} and \{von Maydell\}, Djuna and Effenberger, \{Audrey H.\} and Oyku Cerit and Wen, \{Hsin Lan\} and Liwang Liu and Gwyneth Welch and Maeve Bonner and Tsai, \{Li Huei\}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = aug,

day = "4",

doi = "10.1016/j.stem.2022.07.005",

language = "English",

volume = "29",

pages = "1197--1212.e8",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "8",

}

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 2022, 'Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity', Cell Stem Cell, vol. 29, no. 8, pp. 1197-1212.e8. https://doi.org/10.1016/j.stem.2022.07.005

TY - JOUR

T1 - Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

AU - Victor, Matheus B.

AU - Leary, Noelle

AU - Luna, Xochitl

AU - Meharena, Hiruy S.

AU - Scannail, Aine Ni

AU - Bozzelli, P. Lorenzo

AU - Samaan, George

AU - Murdock, Mitchell H.

AU - von Maydell, Djuna

AU - Effenberger, Audrey H.

AU - Cerit, Oyku

AU - Wen, Hsin Lan

AU - Liu, Liwang

AU - Welch, Gwyneth

AU - Bonner, Maeve

AU - Tsai, Li Huei

PY - 2022/8/4

Y1 - 2022/8/4

N2 - Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

AB - Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

KW - APOE

KW - Alzheimer's risk variant

KW - GIRKs

KW - calcium dynamics

KW - forebrain spheroids

KW - lipid droplet

KW - microglia

KW - network-activity

KW - stem cells

UR - https://www.scopus.com/pages/publications/85135411860

U2 - 10.1016/j.stem.2022.07.005

DO - 10.1016/j.stem.2022.07.005

M3 - Article

C2 - 35931030

AN - SCOPUS:85135411860

SN - 1934-5909

VL - 29

SP - 1197-1212.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 8

ER -

Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

Abstract

Keywords

Access to Document

Fingerprint

Cite this