Dataset Information

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology.

ABSTRACT: The accumulation of neurofibrillary tangles (NFTs), which is composed of abnormally hyperphosphorylated tau aggregates, is the classic neuropathology associated with cognitive dysfunction in tauopathies such as Alzheimer's disease (AD). However, there is an emerging theory suggesting that dysregulation in cerebral iron may contribute to NFT formation. Iron is speculated to bind to tau and induce conformational changes of the protein, potentially leading to subsequent aggregation and cognitive decline. Deferiprone (DFP) is a clinically available iron chelator, which has demonstrated potential therapeutic advantages of chelating iron in neurodegenerative disorders, and is currently in clinical trials for AD. However, its effect on tau pathology remains unclear. Here, we report the effects of short-term DFP treatment (4 weeks, 100 mg/kg/daily, via oral gavage) in a mixed-gender cohort of the rTg_(tauP301L)4510 mouse model of tauopathy. Our results revealed that DFP improved Y-maze and open field performance, accompanied by a 28% decrease in brain iron levels, measured by inductively coupled plasma mass spectrometry (ICP-MS) and reduced AT8-labeled p-tau within the hippocampus in transgenic tau mice. This data supports the notion that iron may play a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders that can be modulated by the clinically available metal chelator DFP.

SUBMITTER: Rao SS

PROVIDER: S-EPMC8423882 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology.

Rao Shalini S SS Lago Larissa L Volitakis Irene I Shukla Jay J JJ McColl Gawain G Finkelstein David I DI Adlard Paul A PA

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20210106 2

The accumulation of neurofibrillary tangles (NFTs), which is composed of abnormally hyperphosphorylated tau aggregates, is the classic neuropathology associated with cognitive dysfunction in tauopathies such as Alzheimer's disease (AD). However, there is an emerging theory suggesting that dysregulation in cerebral iron may contribute to NFT formation. Iron is speculated to bind to tau and induce conformational changes of the protein, potentially leading to subsequent aggregation and cognitive de ...[more]

PMID: 33410108

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Project description:BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

Project description:Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model. Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments. Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes. Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.

Dataset Information

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology.

Publications

Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology.

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