Opposing Roles of apolipoprotein E in aging and neurodegeneration
Open accessAbstract
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer’s disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8–10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18–20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE’s role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.
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Apoe knockout plaque-depositing mice still exhibit deposition of Aβ plaques, but the plaques are less compact and do not cause the synaptic and cognitive deficits typical of plaque-depositing mice with Apoe intact.
“Apoe knockout plaque-depositing mice highlight the complexity of the APOE–Aβ interaction, as these mice still exhibit deposition of Aβ plaques, but the plaques are less compact and do not cause the synaptic and cognitive deficits typical of plaque-depositing mice with Apoe intact117,119,122.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [122]
The Results sections on amyloid burden and synaptic integrity report that APP/PSEN1/APOEnull mice retain Aβ deposits, have fewer dense-core plaques, and lack the plaque-adjacent synaptic loss seen in APP/PSEN1 mice. The paper reports improved neuronal responses in adult mice, but it does not establish that these plaque-depositing knockout mice lack cognitive deficits; the Discussion notes age-dependent neuronal dysfunction despite the earlier improvement. No page numbers were available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe process of APOE binding to TREM2 and promoting plaque compaction likely explains why both Apoe knockout and Trem2 knockout plaque-depositing mice exhibit reduced microglial reactivity against Aβ plaques and their plaques are less compact.
“This process is likely to explain why both Apoe knockout and Trem2 knockout plaque-depositing mice exhibit reduced microglial reactivity against Aβ plaques and their plaques are less compact117,119,122,155.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [122]
The Results report reduced glial reactivity and fewer dense-core plaques in APP/PSEN1 mice lacking APOE. The Discussion proposes that inhibition of the APOE–TREM2 pathway could explain the reduced glial reactivity, but does not establish that this pathway causes the change in plaque compaction. The cited paper also does not report the claimed plaque and microglial findings for Trem2-knockout mice. (LLM, conf=0.86)
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Resting-State Functional Connectivity Changes in Aging apoE4 and apoE-KO Mice
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The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease
the Synaptic Health Endpoints Working Group, Colom-Cadena, M., Spires-Jones, T., Zetterberg, H., Blennow, K., Caggiano, A., DeKosky, S. T., Fillit, H., Harrison, J. E., Schneider, L. S., et al. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00588-4 · Cited by 328 · see citing works
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Self-citation
- Authors
- Hudry, E., Klickstein, J., Cannavo, C., Jackson, R., Muzikansky, A., Gandhi, S., Urick, D., Sargent, T., Wrobleski, L., Roe, A. D., Hou, S. S., Kuchibhotla, K. V., Betensky, R. A., Spires-Jones, T., & Hyman, B. T.
- Affiliations
- Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
- Harvard University (US)
- UK Dementia Research Institute (GB)
- Johns Hopkins University (US)
- Centre for Discovery Brain Sciences, UK Dementia Research Institute, and Edinburgh Neuroscience, The University of Edinburgh, Edinburgh, UK
- ORCID
- Venue
- Life Science Alliance
- Publisher
- Life Science Alliance, LLC
- Published
- 2019-02
- Volume
- 2
- Issue
- 1
- Pages
- e201900325
- ISSN
- 2575-1077 (ISSN-L)
- PMC
- PMC6374993
- OpenAlex
- W2914866847
- Cited by
- 30
- References
- 93
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 3
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Life Science Alliance (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- the National Institute of Health/the National Institute on Aging (1K99AG047336-01A1)
- UK Dementia Research Institute
- European Research Council
- Alzheimer’s Research UK (ARUK-SPG2013-1)
- Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund
- Alzheimer’s Society (AS-PG-15b-023)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, Alzheimer's disease, brain aging, neurodegeneration, amyloid plaques, synaptic loss, neuronal excitability, visual evoked potentials, reactive glia, neuroprotection, neurotoxicity
- MeSH terms
- Loss of Function Mutation, Aging, Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Disease Models, Animal, Evoked Potentials, Visual, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neuroglia, Neurons, Regeneration, Synapses, Visual Cortex, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Presenilin-1, 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.
What counts as a claim ›How we measure confidence ›How we check this ›
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