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.

神经原纤维缠结 (NFT) 的积累由异常过度磷酸化的 tau 蛋白聚集体组成，是与阿尔茨海默病 (AD) 等 tau 蛋白病认知功能障碍相关的经典神经病理学。然而，有一种新兴理论表明，大脑铁的失调可能会导致 NFT 的形成。据推测，铁会与 tau 蛋白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。Deferiprone (DFP) 是一种临床可用的铁螯合剂，已证明螯合铁在神经退行性疾病中的潜在治疗优势，目前正在进行 AD 的临床试验。然而，它对 tau 病理学的影响仍不清楚。在这里，我们报告了短期 DFP 治疗（4 周，100 mg/kg/天，通过口服强饲）在 rTg (tauP301L) 4510 tau 蛋白病小鼠模型的混合性别队列中的_效果。我们的结果显示，通过电感耦合等离子体质谱 (ICP-MS) 测量，DFP 改善了 Y 迷宫和开放场表现，同时脑铁水平降低了 28%，并减少了转基因小鼠海马体内 AT8 标记的 p-tau 蛋白。 tau 小鼠。该数据支持这样的观点，即铁可能在 tau蛋白病中发挥神经毒性作用，并且可能是此类疾病的潜在治疗靶点，可以通过临床上可用的金​​属螯合剂 DFP 进行调节。