Microglia‐specific ApoE knock‐out does not alter Alzheimer's disease plaque pathogenesis or gene expression
Open accessAbstract
Previous studies suggest that microglial‐expressed Apolipoprotein E (ApoE) is necessary to shift microglia into a neurodegenerative transcriptional state in Alzheimer's disease (AD) mouse models. On the other hand, elimination of microglia shifts amyloid beta (Aβ) accumulation from parenchymal plaques to cerebral amyloid angiopathy (CAA), mimicking the effects of global APOE*4 knock‐in. Here, we specifically knock‐out microglial‐expressed ApoE while keeping astrocytic‐expressed ApoE intact. When microglial‐specific ApoE is knocked‐out of a 5xFAD mouse model of AD, we found a ~35% increase in average Aβ plaque size, but no changes in plaque load, microglial number, microglial clustering around Aβ plaques, nor the formation of CAA. Immunostaining revealed ApoE protein present in plaque‐associated microglia in 5xFAD mice with microglial‐specific ApoE knockout, suggesting that microglia can take up ApoE from other cellular sources. Mice with Apoe knocked‐out of microglia had lower synaptic protein levels than control mice, indicating that microglial‐expressed ApoE may have a role in synapse maintenance. Surprisingly, microglial‐specific ApoE knock‐out resulted in few differentially expressed genes in both 5xFAD and control mice; however, some rescue of 5xFAD associated neuronal networks may occur with microglial‐specific ApoE knock‐out as shown by weighted gene co‐expression analysis. Altogether, our data indicates that microglial‐expressed ApoE may not be necessary for plaque formation or for the microglial transcriptional shift into a Disease Associated Microglia state that is associated with reactivity to plaques but may be necessary for plaque homeostasis in disease and synaptic maintenance under normal conditions.
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Removing APOE4 specifically from microglia of APOE4/PS19 tauopathy mice rescued a neuroprotective microglial signature.
“removing APOE4 specifically from microglia of APOE4/PS19 tauopathy mice rescued a neuroprotective microglial signature157,158.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [157]
The Discussion (page unavailable) confirms that the authors knocked out Apoe specifically in microglia, but they studied 5xFAD mice, not APOE4/PS19 tauopathy mice. They report few gene-expression changes and no change in disease-associated microglial genes in their model; they explicitly say the role of microglial Apoe knockout in tauopathy models remains to be determined. The claimed rescue of a neuroprotective microglial signature is therefore not supported by this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia-specific Apoe knockout Aβ plaque-depositing mice exhibit largely unchanged microglial and Aβ phenotypes except for slightly larger plaques.
“microglia-specific Apoe knockout Aβ plaque-depositing mice (Box 3) exhibit largely unchanged microglial and Aβ phenotypes except for slightly larger plaques157.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [157]
Reconstitution of APOE expression in microglia only in an Apoe knockout background or microglia-specific knockout of APOE had no effect on amyloid plaque formation or microglial association with plaques.
“However, reconstitution of APOE expression in microglia only in an Apoe knockout background (Mancuso et al, 2024) or microglia-specific knockout of APOE had no effect on amyloid plaque formation or microglial association with plaques (Henningfield et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Henningfield et al, 2022
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- Authors
- Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Green, Kim N.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2021-10-13
- Volume
- 70
- Issue
- 2
- Pages
- 287-302
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC9308171
- OpenAlex
- W3207140476
- Cited by
- 40
- References
- 71
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 12 · 2023: 9 · 2022: 11
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (F31NS111882, R01NS083801)
- National Institute on Aging (F31AG072852, RF1AG065329, F31AG059367, R01AG056768, T32AG00096, U54AG054349)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, amyloid plaques, cerebral amyloid angiopathy, 5xFAD mice, disease-associated microglia, synapse maintenance, gene co-expression network
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Mice, Transgenic, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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