Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer’s Disease
Open accessAbstract
The earliest stages of Alzheimer's disease (AD) are characterized by the formation of mature tangles in the entorhinal cortex and disorientation and confusion when navigating familiar places. The medial entorhinal cortex (MEC) contains specialized neurons called grid cells that form part of the spatial navigation system. Here we show in a transgenic mouse model expressing mutant human tau predominantly in the EC that the formation of mature tangles in old mice was associated with excitatory cell loss and deficits in grid cell function, including destabilized grid fields and reduced firing rates, as well as altered network activity. Overt tau pathology in the aged mice was accompanied by spatial memory deficits. Therefore, tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD.
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Tau pathology can interfere with neuronal circuits, resulting in theta and gamma oscillation deficits long before neurons die.
“Previous studies have shown that tau pathology can interfere with neuronal circuits, resulting in theta and gamma oscillation deficits long before neurons die16,20–23.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [20]
The Results section (page unavailable) reports increased theta power in 30+-month-old EC-Tau mice, but no significant gamma-power difference in any group. The Discussion (page unavailable) links the theta increase to extensive neuronal loss, rather than showing theta and gamma deficits long before neurons die. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAmyloid pathology induces abnormal theta and gamma oscillations, likely due to deficient inhibitory interneuron activity.
“Previous studies show that amyloid pathology induces abnormal theta and gamma oscillations, likely due to deficient inhibitory interneuron activity, not examined here20,49,50.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [20]
The Results section on interneuron firing and oscillations reports increased interneuron firing and theta power in aged EC-Tau mice, but no significant difference in gamma power. The Discussion attributes the theta change to tau pathology and increased inhibitory activity, rather than amyloid pathology and deficient interneuron activity. No page number is available in our copy. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAmyloid pathology induces abnormal theta and gamma oscillations, likely due to deficient inhibitory interneuron activity.
“Previous studies have shown that amyloid pathology induces abnormal theta and gamma oscillations, likely due to deficient inhibitory interneuron activity”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [20]
The Results section (page unavailable) reports increased theta power and increased interneuron firing in aged EC-Tau mice, but no significant difference in gamma power. The Discussion attributes these changes to tau pathology and suggests increased, not deficient, inhibitory activity. The paper therefore does not support the claimed amyloid-driven mechanism and reports contrary findings for gamma and interneuron activity. (LLM, conf=0.90)
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Experimental — accuracy not yet measured
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Cites
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“…and selective atrophy in the EC, which correlates with severe cell loss of more than 70%of layer II and 40%of layer III neurons (Braak and Braak, 1991; Gómez-Isla et al., 1996; Masdeu et al., 2005; Stranahan and Mattson, 2010), and hypometabolism in functional imaging studies (Khan et al., 2014).”
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- Authors
- Fu, H., Rodriguez, G. A., Herman, M., Emrani, S., Nahmani, E., Barrett, G., Figueroa, H. Y., Goldberg, E., Hussaini, S. A., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Hussaini, S. Abid
- Duff, Karen E.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 93
- Issue
- 3
- Pages
- 533-541.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5363269
- OpenAlex
- W2576056287
- Cited by
- 264
- References
- 8
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 25 · 2023: 25 · 2022: 33 · 2021: 38 · 2020: 24 · 2019: 30 · 2018: 32 · 2017: 9 · 2012: 1
- FWCI
- 18.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- NIH (R01NS074874, R01AG050425)
- Alzheimer's Association (2015-NIRG-341570)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau pathology, Alzheimer's disease, medial entorhinal cortex, grid cells, spatial memory impairment, tau tangles, spatial navigation, transgenic mouse model, network activity
- MeSH terms
- Grid Cells, Action Potentials, Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Humans, Interneurons, Mice, Transgenic, Neurons, tau Proteins, Entorhinal Cortex, Tauopathies, Mice, Spatial Memory
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