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ApoE4 upregulates the activity of mitochondria‐associated ER membranes

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Tambini, Marc D, Pera, Marta, Kanter, Ellen, Yang, Hua, Guardia‐Laguarta, Cristina, Holtzman, David, Sulzer, David, Area‐Gomez, Estela +1 more·2016·The EMBO Reports
DOI 10.15252/embr.201540614PMC PMC4718413
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Abstract

In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease. The reason why ApoE4 is a risk factor in Alzheimer's disease is unknown. This study shows that lipoproteins containing ApoE4, but not those containing ApoE3, upregulate the communication between ER and mitochondria at mitochondria‐associated ER membranes (MAM), and may help explain, in part, the role of ApoE4 as a risk factor in the disease. The reason why ApoE4 is a risk factor in Alzheimer's disease is unknown. This study shows that lipoproteins containing ApoE4, but not those containing ApoE3, upregulate the communication between ER and mitochondria at mitochondria‐associated ER membranes (MAM), and may help explain, in part, the role of ApoE4 as a risk factor in the disease.

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  • ApoE4 disrupts brain mitochondrial function via multiple mechanisms.

    “given that ApoE4 disrupts brain mitochondrial function via multiple mechanisms (Chen et al., 2011; Nuriel et al., 2017; Tambini et al., 2016; Zhao et al., 2017b)”

    From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Tambini et al., 2016

    The Introduction and Results and Discussion report that ApoE4-containing astrocyte-conditioned media increased mitochondria-associated ER membrane activity and altered ER–mitochondrial communication in treated cells. They do not establish disruption of mitochondrial function in the brain through multiple mechanisms; the Results and Discussion also report similar respiration in ApoE4- and ApoE3-treated cells. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Increased ER-mitochondrial interactions increase MAM activity in neurons treated with conditioned medium from apoE4- but not apoE3-expressing astrocytes.

    “Increased ER-mitochondrial interactions increase MAM activity in neurons treated with conditioned medium from apoE4- but not apoE3-expressing astrocytes [104].”

    From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [104]

    The Results and Discussion report increased phosphatidylethanolamine synthesis in mouse hippocampal neurons treated with ApoE4 versus ApoE3 astrocyte-conditioned medium, supporting increased MAM-related activity. They do not show that increased physical ER–mitochondrial interactions caused that neuronal effect; the paper says the mechanism is unclear, and its apposition measurement showed only a trend in ApoE4-treated cells. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • MAM are overly activated and both organelles communicate more tightly in cells treated with ApoE4-containing astrocyte-conditioned medium, compared to ApoE3.

    “MAM are overly activated and both organelles communicate more tightly in cells treated with ApoE4-containing astrocyte-conditioned medium, compared to ApoE3 [19].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [19]

    The Introduction and Results and Discussion report significantly increased MAM function and ER–mitochondrial communication with ApoE4-containing medium compared with ApoE3. But if “more tightly” means closer physical apposition, the Results and Discussion report only a nonsignificant trend toward greater ER–mitochondrial co-localization, not an established increase. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • ApoE4 increases susceptibility to Alzheimer's disease rather than determining its development.

    “Being a risk factor, ApoE4 rather increases the susceptibility to AD than determines its development [19].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [19]

  • In ApoE4 mutant mice, mitochondrial phenotypes include increased fusion, disrupted mitophagy, and calcium overload.

    “In ApoE4 mutant mice, mitochondrial phenotypes include increased fusion, disrupted mitophagy, and calcium overload [45–47].”

    From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [47]

    The Abstract and Results and Discussion report increased ER–mitochondrial communication and lipid synthesis in cells treated with ApoE4-containing astrocyte-conditioned media, not mitochondrial phenotypes in ApoE4 mutant mice. Searches for fusion, mitophagy, and calcium overload found no passage reporting those outcomes; the mention of mitofusin 2 concerns a knockout used to test phospholipid synthesis. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Tambini, M. D., Pera, M., Kanter, E., Yang, H., Guardia‐Laguarta, C., Holtzman, D., Sulzer, D., Area‐Gomez, E., & Schon, E. A.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Washington University in St. Louis (US)
Corresponding author
Schon, Eric A
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2015-11-12
Volume
17
Issue
1
Pages
27-36
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.201540614
PMC
PMC4718413
OpenAlex
W2169391157
Cited by
166
References
8
Citations by year
2026: 12 · 2025: 19 · 2024: 16 · 2023: 20 · 2022: 10 · 2021: 17 · 2020: 24 · 2019: 18 · 2018: 9 · 2017: 10 · 2016: 11
FWCI
6.68
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders
  • U.S. National Institutes of Health (K01 AG045335, NS38370, R01 NS090934, R01AG047644)
  • JPB Foundation
  • Parkinson's Disease Foundation
  • The Alzheimer's Drug Discovery Foundation
  • The Ellison Medical Foundation
  • U.S. Department of Defense (W911NF‐12‐1‐9159, W911F‐15‐1‐0169)
  • J. Willard and Alice S. Marriott Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, Alzheimer's disease, mitochondria-associated ER membranes, ER-mitochondria communication, lipoproteins, phospholipid synthesis, cholesterol esters, cholesterol homeostasis, lipid metabolism, astrocyte-conditioned medium, APOE3, familial Alzheimer's disease, sporadic Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Cholesterol, Cholesterol Esters, Endoplasmic Reticulum, Humans, Intracellular Membranes, Lipoproteins, Mitochondria, Phospholipids, Transcriptional Activation, Up-Regulation, Culture Media, Conditioned, Lipid Metabolism, Mice, Apolipoprotein E4

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