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Cited by 122Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyCalcium signaling and nucleotide metabolism

Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

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Parcon, Paul A., Balasubramaniam, Meenakshisundaram, Ayyadevara, Srinivas, Jones, Richard A., Liu, Ling, Shmookler Reis, Robert J., Barger, Steven W., Mrak, Robert E. +1 more·2018·Alzheimer's & Dementia
DOI 10.1016/j.jalz.2017.07.754PMC PMC6613789
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Abstract

Introduction: Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to “coordinated lysosomal expression and regulation” (CLEAR) DNA motifs. Methods: Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. Results: Three TFEB‐regulated mRNA transcripts—SQSTM, MAP1LC3B, and LAMP2—were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. Conclusion: ApoE4‐CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.

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  • This mitochondrial dysfunction partly results from a blockade of mitophagy owing to APOE4-mediated lysosomal dysfunction, leading to accumulation of damaged and dysfunctional mitochondria in APOE4 carriers.

    “in vitro studies have indicated that this mitochondrial dysfunction partly results from a blockade of mitophagy owing to APOE4-mediated lysosomal dysfunction, which leads to an accumulation of damaged and dysfunctional mitochondrial in APOE4 carriers167–169.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [167]

    The Results (page not provided) show that apoE4-expressing cells accumulated mitochondrial proteins, including a marker used for mitophagy, and failed to clear aggregates under starvation. The Discussion interprets this as implying lysosomal dysfunction. The paper does not demonstrate a blockade of mitophagy or show that damaged, dysfunctional mitochondria accumulate in APOE4 carriers; those conclusions go beyond the cell findings. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • APOE4 is associated with impaired autophagy in astrocytes.

    “Previously, others and we have found that APOE4 is associated with impaired autophagy in astrocytes13,14, which is linked to reduced clearance of Aβ plaques and protein aggregates13,14.”

    From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [14]

  • Impaired autophagy in APOE4 astrocytes is linked to reduced clearance of Aβ plaques and protein aggregates.

    “Previously, others and we have found that APOE4 is associated with impaired autophagy in astrocytes13,14, which is linked to reduced clearance of Aβ plaques and protein aggregates13,14.”

    From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [14]

  • This is in line with evidence from brain samples of APOE4 patients showing downregulation of autophagy components and supports the role of astrocyte-mediated autophagy in degradation of Aβ.

    “This is in line with evidence from brain samples of APOE4 patients showing downregulation of autophagy components (Parcon et al, 2018) and supports the role of astrocyte-mediated autophagy in degradation of Aβ (Simonovitch et al, 2016, 2019).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Parcon et al, 2018

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Authors
Parcon, P. A., Balasubramaniam, M., Ayyadevara, S., Jones, R. A., Liu, L., Shmookler Reis, R. J., Barger, S. W., Mrak, R. E., & Griffin, W. S. T.
Affiliations
  • University of Arkansas for Medical Sciences (US)
  • Central Arkansas Veterans Healthcare System (US)
  • Donald W. Reynolds Department of Geriatrics, Reynolds Institute on Aging University of Arkansas for Medical Sciences Little Rock AR USA
  • University of Toledo (US)
Corresponding author
Griffin, W. Sue T.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2017-09-22
Volume
14
Issue
2
Pages
230-242
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1016/j.jalz.2017.07.754
PMC
PMC6613789
OpenAlex
W2758429249
Cited by
122
References
4
Citations by year
2026: 8 · 2025: 24 · 2024: 9 · 2023: 9 · 2022: 21 · 2021: 12 · 2020: 16 · 2019: 16 · 2018: 7
FWCI
7.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Institute on Aging (AG12411)
  • Materials Research Institute, Pennsylvania State University (CNS‐0619069)
  • Windgate Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
APOE ε4, Alzheimer's disease
MeSH terms
Alzheimer Disease, Autophagy, Brain, Cell Line, Transformed, Computer Simulation, Epistasis, Genetic, Female, Genotype, Humans, Lysosomes, Male, Models, Molecular, Protein Binding, RNA, Messenger, Cytokines, Disease Progression, Electrophoretic Mobility Shift Assay, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Apolipoprotein E3, Apolipoprotein E4, Nucleotide Motifs, Molecular Docking Simulation

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