Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild‐type human tau
Open accessAbstract
To investigate how tau affects neuronal function during neurofibrillary tangle (NFT) formation, we examined the behavior, neural activity, and neuropathology of mice expressing wild-type human tau. Here, we demonstrate that aged (>20 months old) mice display impaired place learning and memory, even though they do not form NFTs or display neuronal loss. However, soluble hyperphosphorylated tau and synapse loss were found in the same regions. Mn-enhanced MRI showed that the activity of the parahippocampal area is strongly correlated with the decline of memory as assessed by the Morris water maze. Taken together, the accumulation of hyperphosphorylated tau and synapse loss in aged mice, leading to inhibition of neural activity in parahippocampal areas, including the entorhinal cortex, may underlie place learning impairment. Thus, the accumulation of hyperphosphorylated tau that occurs before NFT formation in entorhinal cortex may contribute to the memory problems seen in Alzheimer's disease (AD).
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The AT8 sites are physiological sites for phosphorylation, but they are not always phosphorylated.
“The AT8 sites are physiological sites for phosphorylation, but they are not always phosphorylated (Kimura et al., 2007;Verwer et al., 2007).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Kimura et al., 2007
The section on PHF1-site phosphorylation identifies AT8 as recognizing tau phosphorylated at Ser202 and Ser205, and reports AT8 immunoreactivity in the studied mice. The Discussion says AT8-site phosphorylation did not increase with aging in those mice, but it does not establish that phosphorylation at these sites is physiological or that the sites are sometimes unphosphorylated. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe AT8 sites (Ser199/Ser202/Thr205) are physiological phosphorylation sites and markers of hyperphosphorylation in Alzheimer's disease.
“The AT8 sites are not only physiological phosphorylation sites (Kimura et al., 2007;Verwer et al., 2007) but also markers of hyperphosphorylation in Alzheimer's disease (Plattner et al., 2006).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Kimura et al., 2007
The Results section (page unavailable) reports AT8 phosphorylation in both adult and aged mice expressing wild-type human tau, without an age-related increase. This supports the narrower point that AT8 phosphorylation can occur without age-related hyperphosphorylation, but the study does not establish that the sites are physiological in normal animals; it also identifies the AT8 sites as Ser202 and Ser205, not Ser199/Ser202/Thr205. The Alzheimer's disease marker claim is attributed to Plattner et al., not Kimura et al., in the citing sentence. (LLM, conf=0.83)
Experimental — accuracy not yet measured
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“Taken together, the accumulation of hyper- phosphorylated tau and synapse loss in aged mice, leading to inhibition of neural activity in parahippocampal areas, including the entorhinal cortex, may underlie place learn- ing impairment.”
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Self-citation
- Authors
- Kimura, T., Yamashita, S., Fukuda, T., Park, J., Murayama, M., Mizoroki, T., Yoshiike, Y., Sahara, N., & Takashima, A.
- Affiliations
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Takashima, Akihiko
- Venue
- The EMBO Journal
- Published
- 2007-11-15
- Volume
- 26
- Issue
- 24
- Pages
- 5143-5152
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2140104
- OpenAlex
- W2053535174
- Cited by
- 144
- References
- 9
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 8
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Institute of Mental Health
- 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
- hyperphosphorylated tau, parahippocampal cortex, place learning, spatial memory, aging, synaptic loss, neurofibrillary tangles, entorhinal cortex, neuronal activity, Alzheimer's disease, memory impairment
- MeSH terms
- Aging, Animals, Behavior, Animal, Brain Mapping, Humans, Magnetic Resonance Imaging, Memory, Mice, Transgenic, Phosphorylation, Synapses, Neurofibrillary Tangles, tau Proteins, Entorhinal Cortex, Maze Learning, Mice
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