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Cited by 129Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease

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Fitz, Nicholas F., Nam, Kyong Nyon, Wolfe, Cody M., Letronne, Florent, Playso, Brittany E., Iordanova, Bistra E., Kozai, Takashi D. Y., Biedrzycki, Richard J. +5 more·2021·Nature Communications
DOI 10.1038/s41467-021-23762-0PMC PMC8184801

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Abstract

Abstract APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.

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  • Many of the lipids differing between APOE4s2G and controls were glycerophospholipids, including many PC and CER species.

    “In agreement with previous postmortem AD studies22,23, many of these lipids were glycerophospholipids, including many phosphatidylcholine (PC) and ceramide (CER) species.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [23]

    The Results section (Fig. 1) reports APOE-dependent differences in phospholipids and includes phosphatidylcholine (PC) among the classes analyzed. It compares AD brains by APOE genotype and APOE3 versus APOE4 lipoproteins, not APOE4s2G with controls; the passages do not report differing ceramide (CER) species. Page numbers are unavailable in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Several AD-risk genes such as TREM2, APOE, ABCA7, ABCA1, and CLU are directly related to lipid metabolism.

    “Several AD-risk genes such as TREM2, APOE, ABCA7, ABCA1, and CLU are directly related to lipid metabolism.26,27,28,29,30,31”

    From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [27]

    The Introduction (page not provided) identifies APOE and TREM2 as AD-risk genes, describes APOE as a lipid transporter, and says TREM2 recognizes lipoproteins. It also describes ABCA1 transferring phospholipids and cholesterol to APOE. The passages from our copy do not establish the claimed lipid-metabolism connection for ABCA7 or CLU, or explicitly identify ABCA1 as an AD-risk gene. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 60 · Cited by 129

Research works printed but not linked: 35

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Authors
Fitz, N. F., Nam, K. N., Wolfe, C. M., Letronne, F., Playso, B. E., Iordanova, B. E., Kozai, T. D. Y., Biedrzycki, R. J., Kagan, V. E., Tyurina, Y. Y., Han, X., Lefterov, I., & Koldamova, R.
Affiliations
University of Pittsburgh (US)
Corresponding author
  • Lefterov, Iliya
  • Koldamova, Radosveta
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-06-07
Volume
12
Issue
1
Pages
3416-3416
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-23762-0
PMC
PMC8184801
OpenAlex
W3170765444
Cited by
129
References
60
Citations by year
2026: 14 · 2025: 38 · 2024: 27 · 2023: 25 · 2022: 19 · 2021: 6
FWCI
7.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association (AARF-16-443213, AG066198, AG057565, 2018-AARG-590509, AG056371)
  • National Institute on Aging (P30AG028383, RF1AG056371, R01AG066198, R01AG057565, R56AG057565, P30AG013319, R01AG077636, P30AG066468)
  • National Institute of Neurological Disorders and Stroke (RF1NS116450, R01NS094396)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE isoforms, APOE3, APOE ε4, phospholipids, lipoproteins, microglial activation, TREM2, amyloid-beta, microglial migration, amyloid-beta uptake, Alzheimer's disease, astrocyte-conditioned medium, microglial transcriptome
MeSH terms
RNA-Seq, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Humans, Male, Membrane Glycoproteins, Mice, Transgenic, Mutation, Phospholipids, Receptors, Immunologic, Amyloid beta-Protein Precursor, Microglia, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4, Presenilin-1

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