Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology
Abstract
Regional progression of neurofibrillary tangles (NFTs) around the hippocampus was traced on thick sections double immunofluorolabeled with RD3 and RD4 antibodies, specific for three- and four-repeat tau, respectively. As reported, the cubic density of all tau-positive neurons was predominant in the entorhinal cortex and cornu ammonis (CA)1, and decreased progressively to the CA2-4 subregions. Among the three isoform profiles (RD3+/4-, RD3+/4+, and RD3-/4+), this regional gradient was replicated with RD3+/4- and RD3+/4+ neurons, while RD3-/4+ neurons exhibited the reverse gradient. Comparison of the subregion pairs confirmed a consistent profile shift along this gradient in every case regardless of the abundance of NFTs. To clarify the underlying mechanism of this regional profile shift, intraneuronal intensity of RD3 and RD4 immunoreactivity (IR) was quantified. Although their intensities were both lower in dendrites than in the soma, this gradient was steeper with RD4, leaving RD3 IR in dendrites. Dendritic arborization was abundant in RD3-/4+ pretangles, attenuated in RD3+/4+ neurons, and further attenuated in RD3+/4- ghost tangles. These findings suggest that dendritic RD4 IR retracts first, leaving RD3 IR in the dendrites. Taken together, this dendrite-oriented retraction initiates the gradual shift from RD3-/4+ pretangle neurons to RD3+/4- ghost tangles by way of RD3+/4+ NFTs. This intraneuronal profile shift may be a basis for the regional gradation featured by the similar profile shift during progression of NFT pathology.
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Neurofibrillary tangles in ECII neurons have been shown to be devoid of 4R-tau, in contrast to NFTs in other hippocampal neurons that have both tau isoforms.
“Importantly, NFTs in ECII neurons have been shown to be devoid of 4R-tau, in contrast to NFTs in other hippocampal neurons that have both tau isoforms (Hara et al., 2013; Iseki et al., 2006).”
From Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis (2020) · cites this paper as Hara et al., 2013
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- Authors
- Hara, M., Hirokawa, K., Kamei, S., & Uchihara, T.
- Affiliations
- Nihon University (JP)
- Nitobe Memorial Nakano General Hospital (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Uchihara, Toshiki
- Venue
- Acta Neuropathologica
- Published
- 2013-02-14
- Volume
- 125
- Issue
- 4
- Pages
- 565-579
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2039088457
- Cited by
- 55
- References
- 60
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 2 · 2013: 4
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22240039, 25430057, 22500325)
- 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 isoforms, four-repeat tau, neurofibrillary tangles, hippocampus, entorhinal cortex, cornu ammonis, dendritic retraction
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Hippocampus, Humans, Male, Middle Aged, Neurons, Neurofibrillary Tangles, tau Proteins, Disease Progression, Protein Isoforms
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