Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse
Introduction
Alzheimer's disease (AD) and Parkinson's disease (PD) are both age-dependent chronic neurological disorders, which pathologically feature protein aggregation and iron accumulation in the affected brain regions (Hare et al., 2013, Ayton et al., 2015a). Despite significant efforts made in the last two decades, there is still no disease modifying treatment for either disease. Most recently, a number of large Phase III clinical trials targeting β-amyloid aggregation, a key feature of AD, were conducted, but failed to demonstrate efficiency (Doody et al., 2013, Doody et al., 2014, Salloway et al., 2014). It is therefore of crucial importance to search for alternative drug targets that may modify the disease symptoms.
Tau protein is extensively implicated in the pathogenesis of AD and considered as a potential drug target (Gozes, 2010). Recent genome-wide association studies identified a significant association between the MAPT locus and sporadic PD (Lei et al., 2010, Nalls et al., 2014), indicating a possible pathological link between tau and PD. The link was supported by pathological findings including the interaction between α-synuclein and tau, and the presence of tau in the Lewy bodies of typical PD (Lei et al., 2010, Arima et al., 1999). Furthermore, tau mutations cause atypical PD syndromes, such as progressive supranuclear palsy, and corticobasal degeneration (Gozes, 2010). While the hyperphosphorylation of tau causes toxicity (Morris et al., 2011), increasing evidence also supports a possible role for functional loss of tau protein in both diseases, as soluble tau is reduced in the affected regions in both disorders (Lei et al., 2012, Kosik et al., 1989, Zhukareva et al., 2001). We previously reported that tau knockout mouse display progressive motor and cognitive behavioral abnormalities, brain weight loss and brain-wide atrophy, loss of key proteins involved in memory formation, neuronal death in substantia nigra (SN), dopamine loss and tyrosine hydroxylase (TH) terminal loss in the caudate-putamen (CPu), as well as iron accumulation in the brain; all of which are features of neurodegeneration (Lei et al., 2012, Lei et al., 2014). Others showed that tau knockout mice (on a different genetic background) display progressive motor and cognitive deficits, in association with a loss of microtubule associated proteins other than tau, and the phenotypes can be prevented by an anti-oxidant (Ma et al., 2014). Although the cognitive phenotypes of tau knockout mouse may depend on its genetic background and food (Gheyara et al., 2014, Morris et al., 2013), the tau knockout mouse remains to be a useful model of aged-associated neurodegeneration which can be utilized for drug discovery.
We have previously shown that 5-chloro-7-iodo-quinolin-8-ol (clioquinol, CQ) treatment prevented the progression of these phenotypes (treatment from 6 months of age), through prevention of iron accumulation in key regions of the brain (Lei et al., 2012). CQ is an 8-hydroxyquinoline derivative that was widely used as an anti-parasitic agent until the 1970s, when it was withdrawn because of suspected severe adverse effects in a Japanese population (Asao, 1979, Nakae et al., 1971). It was rediscovered in 2000s to be a drug candidate for Alzheimer's disease since treatment with CQ rapidly reduced plaques in Tg2576 transgenic mice (Cherny et al., 2001). It was later found that CQ also showed beneficial effects in cellular and animal models of PD (Lei et al., 2012, Kaur et al., 2003, Kaur et al., 2009, Tardiff et al., 2012), Huntington's disease (HD) (Nguyen et al., 2005), cancer (Chen et al., 2007, Ding et al., 2008, Yu et al., 2009), and it can protect against aging sequelae (Wang et al., 2009, Adlard et al., 2014a). It also was tested in a Phase 2 clinical trial in AD, which reported that it was well tolerated and that treatment slowed cognitive deterioration (Ritchie et al., 2003). It is proposed that CQ is neuroprotective, and functions by chaperoning the biometals (Li et al., 2010, Adlard et al., 2008), involved in disease pathogenesis (Ayton et al., 2013a). More specifically, CQ is found to be a copper and zinc ionophore (Adlard et al., 2008), and a moderate iron chelator (Kaur et al., 2003). The second generation of CQ, PBT2, was reported to be safe and beneficial for AD and HD patients in Phase II clinical trials (Lannfelt et al., 2008, Faux et al., 2010). Other iron chelation therapies have also been tested preclinically and clinically for AD and PD, and showed positive outcomes (Kaur et al., 2003, Devos et al., 2014, Ben-Shachar et al., 1991, Zheng et al., 2005a, Zheng et al., 2005b, Kupershmidt et al., 2012, Ayton et al., 2013b, Guo et al., 2013a, Guo et al., 2013b, Zhu et al., 2010, Crapper McLachlan et al., 1991).
Our previous results demonstrating the efficacy of CQ in tau KO mice were from a prevention experimental paradigm, where the drug administration commenced before symptom onset. But a therapy for neurodegenerative disorders will require drug treatment after disease manifestation. So, in the current study, we explored whether CQ treatment to symptomatic (13 months old) tau knockout mice would rescue behavioral, biochemical and neuroanatomical deficits.
Section snippets
CQ rescues behavioral disability of symptomatic tau KO mice
Tau knockout mice commenced CQ therapy (30 mg/kg/day) at 13 months of age and were treated for 5 months. Mice were monitored every three weeks by accelerating rotarod test as well as pole test during the CQ treatment period. The mice were symptomatic at the commencement of the study, displaying impairment in rotarod, pole test and Y-maze, but had normal body weight, when compared to 12-month old wild-type historic controls (Lei et al., 2012, Lei et al., 2014).
CQ treatment did not alter the body
Discussion
Our current study reconfirms the cognitive and motor neurodegenerative phenotype of tau knockout mice at a more advanced age than our previous reports (Lei et al., 2012, Lei et al., 2014). Since we previously demonstrated the phenotype in two separate cohorts (Lei et al., 2012, Lei et al., 2014), here we included only historic controls as dimensional comparators for the phenotype, which is a caveat in estimating the degree of pathology associated with the mutant. Nevertheless, the surprising
Mice and mice tissue preparation
All mice were housed in a conventional animal facility according to standard animal care protocols and fed standard laboratory chow (Meat Free Rat and Mouse Diet, Specialty Feeds, Australia) and tap water ad libitum. All animal procedures were approved by the Florey Institute animal ethics committee (10–017) and were performed in accordance with the National Health and Medical Research Council guidelines. Tau knockout mice (Dawson et al., 2001) and background C57Bl6/SV129 mice were raised under
Competing interests
Drs. Adlard and Finkelstein are shareholders in and paid scientific consultants for Prana Biotechnology Pty Ltd. Dr. Bush is a shareholder in Prana Biotechnology Pty Ltd., Eucalyptus Pty Ltd., Mesoblast Pty Ltd., Brighton Biotech Inc and a paid consultant for Collaborative Medicinal Developments LLC and Brighton Biotech Inc.
Authors' contributions
Scientific concept: PL, AIB. Experimental design: PL, PAA, DIF, AIB. Experiments: PL, SA, ATA, IV, PAA. Manuscript preparation: PL, SA, AIB. Manuscript edit: all authors.
Acknowledgments
Supported by funds from the Australian Research Council, the National Health and Medical Research Council (NHMRC) of Australia, the Cooperative Research Center for Mental Health, Alzheimer's Australia Dementia Research Foundation, and Melbourne Early Career Researcher Grants Scheme. Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.
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2021, Journal of Biological ChemistryCitation Excerpt :Our group has described that tau mediates the trafficking of APP to the cell surface where APP promotes iron efflux by stabilizing ferroportin; thus, tau ablation significantly attenuates iron transport in vitro and in vivo (9, 311–313). Soluble tau is reported to be reduced in Alzheimer’s patients (314–319), and such loss in mice causes iron accumulation and, consequently, neurodegeneration, which can be rescued by iron chelation or antioxidant supplementation (9, 320, 321). We and others reported that pharmacologically suppressing tau expression with lithium (322, 323) caused APP- and tau-dependent iron accumulation, and indeed the treatment of human subjects with lithium increased iron in their hippocampus and substantial nigra (312, 324).
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