Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse

Abstract

Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippocampus, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…8), which is also pathology of AD [28,39]. Lowering brain iron has been shown to reduce memory deficits and neuronal loss in AD animal models and in a clinical trial [11,14,[40][41][42][43]. We recently reported that elevated brain iron, as reflected by elevated cerebrospinal fluid ferritin levels, is associated with accelerated cognitive decline [44], highlighting the role of iron in AD progression.…”

“…atrophy [11][12][13], caused by brain iron [11,14]. It is thus unclear how the reduction of tau can both precipitate cognitive decline and protect against Aβ-induced toxicity.…”

“…In this role, tau facilitates the export of iron as APP stabilizes surface ferroportin, which is the obligate iron export protein [11]. As a result, tau KO mice develop irondependent neurodegeneration after the age of 6 months, which can be rescued by iron chelation [11,14]. This is important because cortical iron elevation has also been implicated in AD pathogenesis [17].…”

The novel mitochondrial iron chelator 5-((methylamino)methyl)-8-hydroxyquinoline protects against mitochondrial-induced oxidative damage and neuronal death

“…The ancient and antiprotozoal drug clioquinol (vioform, 5-chloro-7-iodo-8-hydroxyquinoline) was shown to prevent MPTP-induced neurotoxicity in mice and reversed the motor deficits in tau KO mice [23,24], and blood-brain barrier-permeable chelators VK28 and M30 prevented the neurotoxicity induced by 6-OHDA and MPTP [25][26][27]. In addition, orally given M30 prevented the loss of tyrosine hydroxylase (TH)-positive neurons and attenuated iron accumulation and microglial activation in…”

Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration

“…For example, the 8-hydroxyquinoline-derived metal ionophores clioquinol and PBT2 have been demonstrated to traffic copper and zinc into cells, prevent Aβ toxicity in vitro, decrease extracellular Aβ levels in vivo and improve the behavioral phenotype of AD model mice [172][173][174][175]. Clioquinol also effectively restored iron levels and reversed cognitive deficits in tau knockout mice, which develop symptoms consistent with both AD and PD [170,176]. Pyrrolidine dithiocarbamate, another copper ionophore, is similarly protective in the APP/PS1 mouse model of AD [177].…”