Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo
Open accessAbstract
The coexistence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the neocortex is linked to neural system failure and cognitive decline in Alzheimer's disease. However, the underlying neuronal mechanisms are unknown. By employing in vivo two-photon Ca 2+ imaging of layer 2/3 cortical neurons in mice expressing human Aβ and tau, we reveal a dramatic tau-dependent suppression of activity and silencing of many neurons, which dominates over Aβ-dependent neuronal hyperactivity. We show that neurofibrillary tangles are neither sufficient nor required for the silencing, which instead is dependent on soluble tau. Surprisingly, although rapidly effective in tau mice, suppression of tau gene expression was much less effective in rescuing neuronal impairments in mice containing both Aβ and tau. Together, our results reveal how Aβ and tau synergize to impair the functional integrity of neural circuits in vivo and suggest a possible cellular explanation contributing to disappointing results from anti-Aβ therapeutic trials.
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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 [21]
The Results section ('Aβ promotes neuronal hyperactivity while tau suppresses activity'; page unavailable) reports markedly reduced cortical neuronal activity in tau-model mice, supporting the claim that tau interferes with neural circuits. The paper measures neuronal calcium activity, not theta or gamma oscillations, and these passages do not establish that the deficits occur long before neuronal death. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMice expressing human wildtype tau or human tau with a P301L mutation have greater percentages of silent neurons, based on in vivo calcium imaging.
“Mice expressing human wildtype tau or human tau with a P301L mutation have greater percentages of silent neurons, based on in vivo calcium imaging (Busche et al., 2019).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Busche et al., 2019
Overexpression of either wild-type tau or human P301L-mutant tau inhibits neural network activity independent of fibril formation.
“Recent studies have found that overexpression of either wild-type tau or human P301L-mutant tau inhibits neural network activity independent of fibril formation.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [30]
Turning off overexpression of wild-type or P301L-mutant tau attenuates inhibition of network activity, which is associated with soluble tau but not fibrillar tau.
“Turning off their overexpression attenuates the inhibition of network activity, which is associated with soluble tau but not fibrillar tau [30].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [30]
Soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau, including NFTs.
“These findings indicate that soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau (including NFT), the “tau we can see”.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [30]
Tau-induced suppression of neural networks can be relieved by turning off transgene expression, with restoration time consistent with soluble tau half-life, not fibrillar tau.
“Tau-induced suppression of neural networks can be relieved by turning off expression of the transgene, leading to rapid restoration of function in a time frame consistent with the half-life of soluble tau protein, not fibrillar tau.”
From All the Tau We Cannot See (2023) · cites this paper as [24]
Calcium imaging reveals suppressed network activity in presence of tau overexpression independent of fibril formation.
“In another example of this same principle, calcium imaging using multiphoton microscopy reveals suppressed network activity in the presence of tau overexpression (in this case either wild-type tau or P301L tau), independent of fibril formation (23, 24).”
From All the Tau We Cannot See (2023) · cites this paper as [24]
Neurofibrillary tangles are an Alzheimer's disease hallmark and principally consist of tau, a microtubule-associated scaffold protein.
“Neurofribrillary tangles are also considered an AD hallmark and principally consist of tau, which is a microtubule-associated scaffold protein [22].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [22]
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Astrocytic and neuronal apolipoprotein E isoforms differentially affect neuronal excitability
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“Neurofribrillary tangles are also considered an AD hallmark and principally consist of tau, which is a microtubule-associated scaffold protein [22].”
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- Authors
- Busche, M. A., Wegmann, S., Dujardin, S., Commins, C., Schiantarelli, J., Klickstein, N., Kamath, T. V., Carlson, G. A., Nelken, I., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- McLaughlin Research Institute (US)
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Busche, Marc Aurel
- Hyman, Bradley T.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-12-17
- Volume
- 22
- Issue
- 1
- Pages
- 57-64
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6560629
- OpenAlex
- W2903957639
- Cited by
- 413
- References
- 53
- Citations by year
- 2026: 34 · 2025: 62 · 2024: 60 · 2023: 58 · 2022: 56 · 2021: 52 · 2020: 55 · 2019: 36
- FWCI
- 24.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DZNE Pub (submittedVersion)
- Funders
- National Institute on Aging (RF1AG058674, P50AG005134, P30AG062421)
- 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
- tau protein, amyloid-beta, Alzheimer's disease, neurofibrillary tangles, neuronal silencing, neuronal hyperactivity, soluble tau, anti-amyloid therapy, two-photon calcium imaging
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Nerve Net, Neurons, Neurofibrillary Tangles, tau Proteins, Mice, Plaque, Amyloid
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