Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy
Open accessAbstract
Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer's disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death.
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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).”
From CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy (2012) · cites this paper as [14]
The section “rTg4510 Brain Suffers Dramatic Neuron Loss with Regional Vulnerability” reports that CA1 neuron loss begins by 5.5 months and reaches 82% by 8.5 months. But it does not identify CA1 as the most affected area: dentate gyrus loss begins earlier, at 2.5 months, and reaches 85% by 8.5 months. The supplied copy does not identify a page for these findings. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFrom 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).”
Neuronal loss appears to be independent of tangle formation in some transgenic mouse models.
“However, neuronal loss appears to be independent of tangle formation in some transgenic mouse models (12)(13)(14).”
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- Authors
- Spires, T. L., Orne, J. D., SantaCruz, K., Pitstick, R., Carlson, G. A., Ashe, K. H., & Hyman, B. T.
- Affiliations
- Massachusetts General Hospital (US)
- University of Minnesota (US)
- McLaughlin Research Institute (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 168
- Issue
- 5
- Pages
- 1598-1607
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1606598
- OpenAlex
- W1965709917
- Cited by
- 401
- References
- 48
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 16 · 2023: 25 · 2022: 13 · 2021: 12 · 2020: 33 · 2019: 18 · 2018: 25 · 2017: 24 · 2016: 20 · 2015: 20 · 2014: 26 · 2013: 30 · 2012: 25
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG08487)
- National Institute on Aging (AG-08487, R01AG026249, AG00277, R01AG008487, AG26249, T32AG000277, P50AG005134)
- 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
- tauopathy, neurofibrillary tangles, neuronal loss, P301L tau mutation, PHF1, hippocampus, dentate gyrus, striatum, Alzheimer's disease, neurodegeneration
- MeSH terms
- Aging, Animals, Brain, Disease Models, Animal, DNA-Binding Proteins, Membrane Proteins, Mice, Transgenic, Microtubule-Associated Proteins, Neurofibrils, Neurons, Nuclear Proteins, Time Factors, Transcription Factors, Biomarkers, Neurofibrillary Tangles, tau Proteins, Gene Silencing, Tauopathies, Mice, t-Complex Genome Region, Polycomb-Group Proteins
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