Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
Open accessAbstract
The ε4 allele of apolipoprotein E ( APOE ) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4 -associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques—fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics—with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4 -driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.
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Previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.
“However, previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [48]
The Results section (‘Hypermetabolism in the hippocampal formation of APOE4 mice’; page unavailable) reports no significant metabolic difference in young APOE4 versus APOE3 mice. It finds increased cerebral blood volume, an indicator of metabolism, only in the older APOE4 mice. The Introduction mentions increased imaging responses in some human APOE4 carriers but does not establish the claimed finding in young individuals. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredAn early hypermetabolism may drive AD pathology, including amyloid production and aggregation as well as tau phosphorylation and accumulation, which leads to neurodegeneration.
“The reason may be that an early hypermetabolism drives AD pathology, including amyloid production and aggregation as well as tau phosphorylation and accumulation, which leads to neurodegeneration [48].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [48]
The Discussion proposes that APOE4-associated hyperactivity may drive Aβ and tau accumulation, followed by neurodegeneration, and reports that increased neuronal activity raises Aβ production. It does not specifically link hyperactivity to tau phosphorylation or establish that it causes amyloid aggregation. The proposed sequence is a hypothesis, not a demonstrated outcome in these mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE4 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 Nuriel et al., 2017
The Results section (“Increased energy-related metabolites in APOE4 EC”; page unavailable) reports APOE4-associated changes in mitochondrial and energy-related metabolites in aged mice. It does not establish that ApoE4 disrupts mitochondrial function via multiple mechanisms; it interprets those changes as correlates of hypermetabolism and neuronal hyperactivity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged APOE-targeted replacement mice.
“prior studies demonstrating that APOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged mice using APOE-targeted replacement mice (Hunter et al., 2012; Lamoureux et al., 2021; Nuriel et al., 2017)”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Nuriel et al., 2017
The Introduction (page not given) reports increased activity in the hippocampal formation of aged APOE4-targeted replacement mice, especially the entorhinal cortex. The Discussion reports an age-associated seizure phenotype, but the paper does not establish a decreased seizure threshold; its Results found no significant difference between APOE3 and APOE4 mice in NMDA-evoked seizure-like discharges. (LLM, conf=0.89)
Experimental — accuracy not yet measuredSeveral studies using APOE4 KI mouse models that do not yet show features of neurodegeneration observed a hypermetabolism caused by APOE4.
“Further, several studies using APOE4 KI mouse models, that do not yet show features of neurodegeneration, observed a hypermetabolism caused by APOE4 [47,48].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [48]
The neuronal hyperactivity observed appears to be primarily localized to the EC within the hippocampal formation.
“the neuronal hyperactivity that we observed appears to be primarily localized to the EC within the hippocampal formation33.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [33]
Young APOE4 carriers or APOE4-knock-in mice with no apparent neurodegenerative pathology show increased brain metabolism and activity.
“Interestingly, several studies in young APOE4 carriers or in APOE4-knock-in mice with no apparent neurodegenerative pathology, revealed increased brain metabolism and activity (Filippini et al., 2009; Evans et al., 2017; Nuriel et al., 2017; Venzi et al., 2017), indicating that the APOE4 effect on brain energy metabolism may differ depending on the degree of pathology.”
From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Nuriel et al., 2017
Inhibitory neurons express higher levels of APOE4.
“However, it has been shown that inhibitory neurons express higher levels of APOE4, and the proportion of inhibitory interneurons could be correlated with AD disease progression [4,34,48]”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [48]
The Results section on hyperexcitability and reduced inhibitory tone reports weaker inhibitory input to excitatory neurons in APOE4 mice, not higher APOE4 expression in inhibitory neurons. Searches for inhibitory-neuron expression and interneuron comparisons found no passage in our copy measuring or comparing APOE4 expression by neuron type; page numbers were not available. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe proportion of inhibitory interneurons could be correlated with AD disease progression.
“However, it has been shown that inhibitory neurons express higher levels of APOE4, and the proportion of inhibitory interneurons could be correlated with AD disease progression [4,34,48]”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [48]
The Results section reports reduced inhibitory synaptic currents in APOE4 mice, and the Discussion attributes reduced inhibitory tone to diminished responsiveness to GABAergic inputs. Neither passage addresses the proportion of inhibitory interneurons or its correlation with Alzheimer’s disease progression (searched: interneuron proportion and disease progression). (LLM, conf=0.76)
Experimental — accuracy not yet measuredAged apoE4-KI mice had increased field potential synchrony and pyramidal cell firing in the entorhinal cortex.
“A recent study found that aged apoE4-KI mice had increased field potential synchrony and pyramidal cell firing in the entorhinal cortex [174].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [174]
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References 83 · Cited by 181
- Authors
- Nuriel, T., Angulo, S. L., Khan, U., Ashok, A., Chen, Q., Figueroa, H. Y., Emrani, S., Liu, L., Herman, M., Barrett, G., Savage, V., Buitrago, L., Cepeda-Prado, E., Fung, C., Goldberg, E., Gross, S. S., Hussaini, S. A., Moreno, H., Small, S. A., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- SUNY Downstate Health Sciences University (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Moreno, Herman
- Small, Scott A.
- Duff, Karen E.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-11-13
- Volume
- 8
- Issue
- 1
- Pages
- 1464-1464
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5684208
- OpenAlex
- W2767500419
- Cited by
- 181
- References
- 83
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 23 · 2023: 23 · 2022: 24 · 2021: 25 · 2020: 16 · 2019: 19 · 2018: 7
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, 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)
- UCL Discovery (University College London) (submittedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- BrightFocus Foundation (A2014200F)
- Cure Alzheimer's Fund
- National Institute on Aging (AG050425, AG048408, AG047797, AG051556)
- National Heart, Lung, and Blood Institute (HL87062, R37HL087062)
- National Institute of Neurological Disorders and Stroke (NS071836, AG048408)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD067244)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, Alzheimer's disease, neuronal hyperactivity, inhibitory tone, GABAergic inhibition, entorhinal cortex, aged mice, genetic risk factors, excitatory neurons, prodromal Alzheimer's disease, brain metabolomics
- MeSH terms
- Aging, Alzheimer Disease, Animals, Energy Metabolism, Fatty Acids, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Mice, Transgenic, Neurons, Entorhinal Cortex, Mice, Apolipoprotein E3, Apolipoprotein E4, Brain Waves
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