Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
Open accessAbstract
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.
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The rTg4510 mouse model specifically expresses tau in the forebrain without amyloid plaques.
“A mouse model of tauopathy (rTg4510) has been developed that specifically expresses tau in the forebrain but without amyloid plaques”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Santacruz et al., 2005
Behavioural and histological studies of the rTg4510 mouse have demonstrated cognitive deficits in learning and motor tasks and marked atrophy of brain regions known to be selectively vulnerable to AD such as the hippocampus and frontal cortex.
“Behavioural and histological studies of the rTg4510 mouse have demonstrated cognitive deficits in learning and motor tasks and marked atrophy of brain regions known to be selectively vulnerable to AD such as the hippocampus and frontal cortex (Santacruz et al., 2005).”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Santacruz et al., 2005
The rTg4510 mouse mimics features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus.
“The rTg4510 mouse mimics the features of clinical neurodegenerative diseases such as Alzheimer's disease with cognitive deficits, NFT formation and neuronal loss in the forebrain and hippocampus (Ramsden et al., 2005, Santacruz et al., 2005).”
From In vivo imaging of tau pathology using multi-parametric quantitative MRI (2015) · cites this paper as Santacruz et al., 2005
Mutant tau expression in rTg4510 mice starts around postnatal day 7 and peaks at 1 month of age.
“Mutant tau expression starts around postnatal day 7 and peaks at 1 month of age (34,35).”
From 2.5 months onward, phosphorylated tau protein and neuronal loss can be detected in the forebrain of rTg4510 mice.
“From 2.5 months onward, phosphorylated tau protein and neuronal loss can be detected in the forebrain of these mice (14,34,35).”
In rTg4510 mice, tau with the P301L mutation is over-expressed in the forebrain driven by the CaMKII promoter.
“In rTg4510 mice (34,35), tau with the mis-sense mutation P301L, found in some FTDP-17 cases (36), is over-expressed in the forebrain driven by the calcium-calmodulin kinase II (CaMKII) promoter.”
Substantial neurodegeneration is observed after 5 months of age in rTg4510 mice, being most apparent in the hippocampal CA1 area.
“Substantial neurodegeneration is observed after 5 months of age, being most apparent in the hippocampal CA1 area (14,34,35).”
In rTg4510 mice, age-dependent loss of neurons and progressive cognitive dysfunction closely mimic the clinical features of tauopathy.
“In rTg4510 mice (34,35), the age-dependent loss of neurons and progressive cognitive dysfunction closely mimic the clinical features of tauopathy.”
Soluble tau, rather than NFTs, is the pathologic tau species.
“Given the evidence that soluble tau, rather than NFTs, is the pathologic tau species (Santacruz et al., 2005, Yoshiyama et al., 2007, Kopeikina et al., 2012, Lasagna-Reeves et al., 2012, Polydoro et al., 2014, Ghag et al., 2018)”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Santacruz et al., 2005
The neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau.
“suggesting that the neurodegeneration observed in these models reflects toxicity of soluble, non-aggregated forms of tau, and may recapitulate early stages of the abnormal metabolism and toxicity of tau [11–14].”
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 [26]
In Tg4510 mice, suppression of the P301L tau transgene leads to unchanged tangle number, cessation of neuronal loss, and improved cognitive performance.
“Intriguingly, suppression of the transgene at that point leads to a striking change in phenotype: The tangles remain unchanged in number (for at least 6 weeks), neuronal loss essentially ceases, and the cognitive performance of the animals improves remarkably.”
From All the Tau We Cannot See (2023) · cites this paper as [18]
NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models express 4R tau with P301L or P301S mutations.
“In contrast, NFTs readily form in transgenic mice that express human tau containing mutations associated with FTLD; the most commonly used models being those that express 4R tau with P301L or P301S mutations[49, 91, 92, 135, 177].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [135]
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“Recent work suggests that Tau amyloid formation may actually be a protectivemechanism that allows potentially toxic Tau intermediates to self-chaperone and sequester themselves into less toxic entities within long-lived neurons (Eisenberg and Jucker, 2012; Oddo et al., 2004; Santacruz et al., 2005).”
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Self-citation
- Authors
- SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M., Orne, J., Janus, C., Mariash, A., Kuskowski, M., Hyman, B., Hutton, M., & Ashe, K. H.
- Affiliations
- University of Minnesota (US)
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
- Corresponding author
- SantaCruz, K.
- Lewis, J.
- Ashe, K. H.
- ORCID
- Venue
- Science
- Published
- 2005-07-15
- Volume
- 309
- Issue
- 5733
- Pages
- 476-481
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC1574647
- OpenAlex
- W2135309154
- Semantic Scholar
- 213e98528b0a0d2c141035b1b70266409044bd37
- Cited by
- 2,014
- References
- 26
- Citations by year
- 2026: 45 · 2025: 71 · 2024: 93 · 2023: 104 · 2022: 96 · 2021: 99 · 2020: 141 · 2019: 92 · 2018: 109 · 2017: 115 · 2016: 85 · 2015: 103 · 2014: 109 · 2013: 96 · 2012: 107
- FWCI
- 51.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns046355-03)
- U.S. Public Health Service (R01-026252)
- National Institute on Aging (R01AG026249, R01AG008487, P01AG015453, R01AG026252, T31-AG00277, P50AG005134)
- National Institute of Neurological Disorders and Stroke (R01NS082672, R01-NS046355, R01-NS46355, R01NS033249)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, neurofibrillary tangles, tauopathy, memory impairment, cognitive decline, neuronal loss, transgenic mouse model, age-related neurodegeneration
- MeSH terms
- Aging, Animals, Atrophy, Brain, Cognition, Doxycycline, Hippocampus, Humans, Memory, Mice, Transgenic, Neuronal Plasticity, Neurons, Organ Size, Phosphorylation, RNA, Messenger, Solubility, Neurofibrillary Tangles, tau Proteins, Disease Progression, Maze Learning, Neurodegenerative Diseases, Mice
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