Targeting metals rescues the phenotype in an animal model of tauopathy

Abstract

Tauopathies are characterized by the pathological accumulation of the microtubule associated protein tau within the brain. We demonstrate here that a copper/zinc chaperone (PBT2, Prana Biotechnology) has rapid and profound effects in the rTg(tauP301L)4510 mouse model of tauopathy. This was evidenced by significantly improved cognition, a preservation of neurons, a decrease in tau aggregates and a decrease in other forms of "pathological" tau (including phosphorylated tau and sarkosyl-insoluble tau). Our data demonstrate that one of the primary mechanisms of action of PBT2 in this model may be driven by an interaction on the pathways responsible for the dephosphorylation of tau. Specifically, PBT2 increased protein levels of both the structural and catalytic subunits of protein phosphatase 2A (PP2A), decreased levels of the methyl esterase (PME1) that dampens PP2A activity, and increased levels of the prolyl isomerase (Pin1) that stimulates the dephosphorylation activity of PP2A. None of these effects were observed when the metal binding site of PBT2 was blocked. This highlights the potential utility of targeting metal ions as a novel therapeutic strategy for diseases in which tau pathology is a feature, which includes conditions such as frontotemporal dementia and Alzheimer's disease.

RETRACTED: The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy1

“…Animal models of tauopathy such as JNPL tauP301L [54] and rTg4510 [55], along with APP/PS1 (AD model) [19,56] and mouse models of PD [57] have provided valuable insights in assessing the efficacy of targeting metals as a therapy for neurodegenerative diseases. For example, the iron chelator deferoxamine improved cognitive function in JNPL tauP301L and APP/PS1 [19,54,56].…”

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

“…The influence of zinc on tau pathology was further confirmed when mice with advanced pathology were treated with a copper/zinc chaperone. This caused increased PP2A activity, and was sufficient to improve memory, to decrease tau pathology and to prevent neurodegeneration [183] . This highlights the potential value of targeting zinc in pathological conditions in which tau pathology is present.…”

Zn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?

“…In that study, the copper ionophore compound had profound effects on modulating the phenotype of those animals (including an inhibition of GSK3ß, a decrease in Aβ multimers and the phosphorylation of tau; and an improvement in cognitive performance). Together with other studies utilising metal ionophore compounds, such as CQ [32] and PBT2 [18,20] in AD models; PBT2 [31] and Cu(GTSM) [29] in a tauopathy model; and PBT2 in models of HD [23], ageing [22] and traumatic brain injury [30]—these reports demonstrate the potent nature of compounds that modulate metal ion homeostasis in various models of human disease.…”

“…This study represented a proof of principle investigation into the use of compounds that have been variably referred to as “chelators”, “chaperones”, “ionophores”, and “metal–protein attenuating compounds”. Whilst the nomenclature has varied, this broad class of compounds have been demonstrated to facilitate the redistribution of metals within the brain and to improve the phenotype in animal models of ageing, Alzheimer’s disease (AD), and Huntington’s disease (HD) [18,19,20,21,22,23,24,25,26,27,28,29,30,31]. The historical long-term use of CQ in human populations, however, has been associated with a number of potential significant side effects that has limited the ongoing use of CQ.…”