Pimozide reduces toxic forms of tau in TauC3 mice via 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Abstract

In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…A recent phase II, multicenter, double-blind, randomized clinical trial has shown an improvement in cognitive performance of schizophrenic patients treated with NAP (AL-108; 5 and 30 mg/day, intranasally) versus placebo-treated patients [255]. These pieces of evidence corroborate findings showing that several autophagy inducers, such as lithium, rapamycin, and Food and Drug Administration (FDA) approved antipsychotic drugs are effective to treat psychosis including schizophrenia [59,60,61,62,109,256,257,258,259,260]. Notably, high-throughput image-based screens performed by Zhang et al (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers.…”

“…Notably, high-throughput image-based screens performed by Zhang et al (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. In particular, pimozide provides an mTOR-independent autophagy induction, because it directly activates AMPK1, which in turn promotes autophagy through the phosphorylation of ULK1 [260]. In contrast, chlorpromazine, which is a typical antipsychotic agent, induces autophagy by inhibiting the Akt/mTOR pathway [59].…”

“…Most reports evidenced autophagy induction by neuroleptics indirectly, only by measuring the degradation of autophagy-dependent substrates. For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD [260]. Again, the effects of two typical antipsychotics, trifluoperazine and haloperidol, on autophagy have been demonstrated indirectly [262,263].…”

Autophagy induction in the treatment of Alzheimer's disease

“…There is more support to the involvement of autophagy in the therapeutic effect of calcium blockers in AD. It was shown that these agents positively affect Aβ burden and tau phosphorylation in vivo and in vitro in parallel with autophagy induction, and that autophagy silencing in vitro abrogates some of these beneficial effects of calcium blockers (Bharadwaj et al, ; Kim et al, ; Steele et al, ). Accordingly, several lines of evidence demonstrate the involvement of autophagy in the therapeutic effect of statins in AD.…”

New Insight into Alzheimer’s Disease via Caspase 3-cleaved Tau: Pathogenic Role in Tau Oligomer Formation and Memory Deficits

“…In addition, soluble oligomers and detergent-insoluble small aggregates of tau can be detected in TauC3 mouse brains at a similar time point to that of the start of the memory deficits [32]. Moreover, when tau oligomers and aggregates are removed by treatment with aggregation blockers, such as methylene blue and Congo-red [32] or an autophagy inducer, such as rapamycin and pimozide memory [34] and synaptic function can be rescued (Figure 1). Similar data are also observed in an apoptosin-induced caspase-cleaved tau transgenic mouse model.…”