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

Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. doi: 10.1016/j.stem.2022.07.005.

Authors

Matheus B Victor¹, Noelle Leary¹, Xochitl Luna¹, Hiruy S Meharena¹, Aine Ni Scannail¹, P Lorenzo Bozzelli¹, George Samaan¹, Mitchell H Murdock¹, Djuna von Maydell¹, Audrey H Effenberger¹, Oyku Cerit¹, Hsin-Lan Wen¹, Liwang Liu¹, Gwyneth Welch¹, Maeve Bonner¹, Li-Huei Tsai²

Affiliations

¹ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: lhtsai@mit.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease*
Apolipoprotein E3 / genetics
Apolipoprotein E4* / genetics
Humans
Microglia
Neurons

Substances

Apolipoprotein E3
Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding