Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT‐deleted (DM) tau mouse model
Open accessAbstract
In Alzheimer's disease, the phosphorylation of tau is a critical event preceding the formation of neurofibrillary tangles. Previous work exploring the impact of a dopamine blocking antipsychotic on tau phosphorylation in a tau transgenic model suggested that extracellular dopamine may play a regulatory role in the phosphorylation state of tau. In order to test this hypothesis, and in order to develop a mouse model of impaired dopamine metabolism and tauopathy, an extant P301L transgenic tau model of Alzheimer's disease and a novel P301L/catechol‐O‐methyltransferase deleted model (DM mouse) were treated with the norepinephrine reuptake inhibitor reboxetine, and prefrontal dopamine concentrations and the phosphorylated state of tau was quantified. In two experiments, male and female P301L+/+//COMT+/+ and P301L+/+//COMT−/− (DM) mice were treated with reboxetine 20 mg/kg IP. In one experiment, acutely following reboxetine injection, the prefrontal cortex of mice were microdialyzed for dopamine, and its metabolites, 3,4‐dihydroxyphenylacetic acid and homovanillic acid, utilizing the MetaQuant technique. In another experiment, acutely following reboxetine injections, tau phosphorylation was quantified in the frontal cortex, striatum, and hippocampus of the mice. Reboxetine injections were followed by significant increases from baseline in extracellular dopamine concentrations in P301L and DM mice, with significantly higher peak levels in the DM mice. Treatment was also followed by increases in tau phosphorylation spread throughout brain regions, with a larger impact on female mice. Extracellular dopamine concentrations exert an influence on the phosphorylation state of tau, with surges in dopamine associating with acute increases in tau phosphorylation. image
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Dopamine surges in the extracellular space increase ptau.
“Though recent data suggests that dopamine surges in the extracellular space increase ptau (32), the physiological relevance of tau-induced increased levels of DAT1 in the context of AD-type amyloidosis will need further study.”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [32]
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Koller, E. J., Ibanez, K. R., Vo, Q., McFarland, K. N., Gonzalez De La Cruz, E., Zobel, L., Williams, T., Xu, G., Ryu, D., Patel, P., et al. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12779 · Cited by 23 · see citing works
- Authors
- Koppel, J., Jimenez, H., Adrien, L., H. Chang, E., Malhotra, A. K., & Davies, P.
- Affiliations
- Feinstein Institute for Medical Research (US)
- The Litwin‐Zucker Research Center for the Study of Alzheimer's Disease The Feinstein Institute for Medical Research Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Manhasset New York USA
- Corresponding author
- Koppel, Jeremy
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2018-11-12
- Volume
- 148
- Issue
- 1
- Pages
- 127-135
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC6758923
- OpenAlex
- W2890071606
- Cited by
- 22
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 3
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Foundation of America
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- tau phosphorylation, dopamine clearance, reboxetine, norepinephrine reuptake inhibition, extracellular dopamine, Alzheimer's disease, tauopathy, sex differences, neurofibrillary tangles, dopamine metabolites, prefrontal cortex
- MeSH terms
- Animals, Brain, Catechol O-Methyltransferase, Disease Models, Animal, Dopamine, Female, Humans, Male, Mice, Transgenic, Phosphorylation, tau Proteins, Mice, Knockout, Tauopathies, Mice
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