Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia.
Neurotherapeutics. 2021 Apr;18(2):1081-1094. doi: 10.1007/s13311-020-00972-w. Epub 2021 Jan 6.
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 rTg4510 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.
神经原纤维缠结（NFTs）的积累，由异常过度磷酸化的 tau 聚集物组成，是与tau 病（如阿尔茨海默病）相关的认知功能障碍的经典神经病理学。然而，有一种新兴理论表明，大脑铁的失调可能导致 NFT 的形成。铁被推测与 tau 结合并诱导蛋白质构象变化，可能导致随后的聚集和认知能力下降。地拉罗司（DFP）是一种临床可用的铁螯合剂，它在神经退行性疾病中具有螯合铁的潜在治疗优势，目前正在进行 AD 的临床试验。然而，它对 tau 病理学的影响尚不清楚。在这里，我们报告了在 rTg4510 tau 病模型的混合性别队列中，短期 DFP 治疗（4 周，每天 100mg/kg，口服灌胃）的效果。我们的结果表明，DFP 改善了 Y 迷宫和开阔场表现，同时大脑铁水平降低了 28%，通过电感耦合等离子体质谱法（ICP-MS）测量，以及减少了转基因 tau 小鼠海马体中 AT8 标记的 p-tau。这一数据支持了这样一种观点，即铁可能在 tau 病中发挥神经毒性作用，并且可能是一类可以通过临床可用的金属螯合剂 DFP 来调节的此类疾病的潜在治疗靶点。
