Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease

Abstract

IntroductionThe use of antipsychotic medications in Alzheimer's disease has been associated with an increased risk of mortality in clinical trials. However, an older postmortem literature suggests that those with schizophrenia treated in an era of exclusively conventional antipsychotic medications had a surprisingly low incidence of tau pathology. No previously published studies have investigated the impact of conventional antipsychotic exposure on tau outcomes in a tau mouse model of AD.MethodsIn two experiments, transgenic rTg (tauP301L) 4510 tau mice were treated with either haloperidol or vehicle and phosphotau epitopes were quantified using high-sensitivity tau ELISA.ResultsAfter treatments of 2 and 6 week's duration, mice treated with haloperidol evidenced a significant reduction in tau phosphorylation associated with an inactivation of the tau kinase AMPK.DiscussionThe data suggest that D2 receptor blockade reduces tau phosphorylation in vivo. Future studies are necessary to investigate the impact of this reduction on tau neuropathology.

Dopamine receptor D2 activation suppresses the radiosensitizing effect of aripiprazole via activation of AMPK

“…Indeed, pretreatment with D2R‐specific antagonists did not prevent the apoptosis‐inducing effect of aripiprazole but rather strengthened it, clearly demonstrating that D2R signaling is not responsible for the aripiprazole‐induced apoptosis in breast cancer cells. It has previously been reported that treating mice with haloperidol reduces tau phosphorylation via D2 blockade‐mediated inactivation of AMPK . In this study, breast cancer cells activate the AMPK pathway in response to aripiprazole treatment.…”

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

“…In the current report, we found that in mice homozygous for the P301L transgene, treatment with reboxetine was followed acutely by significant increases in extracellular dopamine concentrations, and contemporaneous increases in the phosphorylation of tau. In our previous work with the Tg4510 mouse, a forebrain expressed P301L model of tauopathy (Santacruz et al 2005), a reduction in phosphorylation of tau was observed following the blockade of the dopamine D 2 receptor with haloperidol (Koppel et al 2016). Similar to the current report, but in a different direction, reductions were observed in PHF1, RZ3, and CP13 phosphotau ratios.…”

“…Previously, we reported on a robust decrease in tau phosphorylation in the cortex and striatum of Tg4510 tau mice following 2 and 6 weeks of treatment with haloperidol, a potent dopamine D 2 receptor blocking antipsychotic (Koppel et al 2016). This result suggests that regional extracellular dopamine concentrations may influence tau phosphorylation patterns and that just as agents that block dopamine signaling reduce tau phosphorylation, therapies that increase dopamine signaling may promote it.…”

The impact of tau hyperphosphorylation at Ser 262 on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest

“…After being activated by LKB1, AMPK kinases stimulate catabolic and inhibit anabolic processes allowing the cells to adapt to hypoxia by adjusting intracellular ATP ( Ramamurthy and Ronnett, 2006 ). It is reported that blocking the AMPK pathway, reduced tau phosphorylation in a tau mouse model of AD, showing a link between activation of the main cellular responsive kinase to ischaemia and generating p-tau, one of the main hallmarks of AD ( Koppel et al., 2016 ).…”