Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT‐deleted (DM) tau mouse model

• Published in: Journal of neurochemistry Vol. 148; no. 1; pp. 127 - 135
• Main Authors: Koppel, Jeremy, Jimenez, Heidy, Adrien, Leslie, H. Chang, Eric, Malhotra, Anil K., Davies, Peter
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-01-2019
• Subjects: Alzheimer's disease; Animals; Antipsychotics; Brain; Brain - metabolism; Catechol; Catechol O-methyltransferase; Catechol O-Methyltransferase - deficiency; Cortex (frontal); Dihydroxyphenylacetic acid; Disease Models, Animal; Dopamine; Dopamine - metabolism; Female; Homovanillic acid; Humans; Kinases; Male; Metabolism; Metabolites; Methyltransferase; Mice; Mice, Knockout; Mice, Transgenic; Neostriatum; Neurodegenerative diseases; Neurofibrillary tangles; Norepinephrine; Phosphorylation; Prefrontal cortex; psychosis; Reboxetine; tau; Tau protein; tau Proteins - metabolism; Tauopathies - metabolism; tau; Alzheimer's disease; dopamine; phosphorylation; psychosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14593

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.
In order to instantiate genetic risk for psychosis in an Alzheimer's disease mouse model, and to explore the impact of acute elevations in dopamine on tau phosphorylation, a catechol‐O‐methyltransferase (COMT) deletion was bred into a mouse model expressing the P301L tau mutation in order to create the DM (P301L/COMT−/−) mouse. P301L and DM mice were treated with reboxetine, blocking the norepinephrine transporter (NET) responsible for the reuptake of dopamine in the cortex. Dopamine surged in the frontal cortex of both DM‐ and P301L‐treated mice, with concentrations significantly higher in mice DM mice that lack COMT, and was associated with elevations in tau phosphorylation in both groups.