Tracking progressive pathological and functional decline in the rTg4510 mouse model of tauopathy
Open accessAbstract
BACKGROUND: The choice and appropriate use of animal models in drug discovery for Alzheimer's disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging. Current models do not fully recapitulate the human disease, and even exhibit various degrees of regional pathological burden and diverse functional alterations. Given this, relevant pathological and functional endpoints must be determined on a model-by-model basis. The present work explores the rTg4510 mouse model of tauopathy as a case study to define best practices for the selection and validation of cognitive and functional endpoints for the purposes of pre-clinical AD drug discovery. METHODS: Male rTg4510 mice were first tested at an advanced age, 12 months, in multiple behavioural assays (step 1). Severe tau pathology and neurodegeneration was associated with profound locomotor hyperactivity and spatial memory deficits. Four of these assays were then selected for longitudinal assessment, from 4 to 12 months, to investigate whether behavioural performance changes as a function of accumulation of tau pathology (step 2). Experimental suppression of tau pathology-via doxycycline administration-was also investigated for its effect on functional performance. RESULTS: Progressive behavioural changes were detected where locomotor activity and rewarded alternation were found to most closely correlate with tau burden and neurodegeneration. Doxycycline initiated at 4 months led to a 50% suppression of transgene expression, which was sufficient to prevent subsequent increases in tau pathology and arrest related functional decline. CONCLUSIONS: This two-step approach demonstrates the importance of selecting assays most sensitive to the phenotype of the model. A robust relationship was observed between pathological progression, development of phenotype, and their experimental manipulation-three crucial factors for assessing the translational relevance of future pre-clinical findings.
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In Tg4510 MAPT transgenics evaluated at 4 and 6 months, memory task impairment and neurodegenerative pathology correspond to sequential activation of neuronal and microglial expression patterns.
“in Tg4510 MAPT transgenics evaluated at 4 and 6 months, respectively, memory task impairment and neurodegenerative pathology correspond to sequential activation of neuronal and microglial expression patterns (Blackmore et al., 2017; Ramsden et al., 2005).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Blackmore et al., 2017
The Results (Study 2; page unavailable) report impaired spatial learning and memory at 4 months and increasing tau burden and atrophy as the mice aged. But the study assessed pathology at 4, 8, and 12 months, not 6 months, and our copy does not report sequential activation of neuronal and microglial expression patterns. Its gene-expression analysis concerned the tau transgene. (LLM, conf=0.88)
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“Similarly, in Tg4510 MAPT transgenics evaluated at 4 and 6 months, respectively, memory task impairment and neurodegenerative pathology correspond to sequential activation of neuronal and microglial expression patterns (Blackmore et al., 2017; Ramsden et al., 2005).”
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Additional file 3 of Altered ribosomal function and protein synthesis caused by tau
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Additional file 2 of Altered ribosomal function and protein synthesis caused by tau
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Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice.
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- Authors
- Blackmore, T., Meftah, S., Murray, T. K., Craig, P. J., Blockeel, A., Phillips, K., Eastwood, B., O’Neill, M. J., Marston, H., Ahmed, Z., Gilmour, G., & Gastambide, F.
- Affiliations
- Eli Lilly (United Kingdom) (GB)
- Corresponding author
- Blackmore, Thomas
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2017-09-20
- Volume
- 9
- Issue
- 1
- Pages
- 77-77
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC5607580
- OpenAlex
- W2755784837
- Cited by
- 66
- References
- 47
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 7 · 2021: 9 · 2020: 14 · 2019: 7 · 2018: 6
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Eli Lilly and Company
- 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 › Neurological Disease Mechanisms and Treatments
- Keywords
- tauopathy, Alzheimer's disease, animal models, tau pathology, neurodegeneration, locomotor hyperactivity, spatial memory impairment, doxycycline, drug discovery
- MeSH terms
- Age Factors, Animals, Mental Disorders, Brain, Cognition Disorders, Discrimination, Psychological, Disease Models, Animal, Doxycycline, Male, Memory, Short-Term, Mice, Transgenic, Motor Activity, Mutation, Psychomotor Performance, Cohort Studies, tau Proteins, Disease Progression, Tauopathies, Mice
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