Ontawong Atcharaporn, Nehra Geetika, Maloney Bryan J, Vaddhanaphuti Chutima S, Bauer Björn, Hartz Anika M S
Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand.
Int J Mol Sci. 2025 May 3;26(9):4352. doi: 10.3390/ijms26094352.
Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kg NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.
阿尔茨海默病（AD）的特征是β-淀粉样蛋白（Aβ）病变，并且与氧化应激密切相关，氧化应激会导致血脑屏障渗漏、肾功能障碍和认知能力下降。我们研究了美国食品药品监督管理局（FDA）批准的抗氧化剂N-乙酰半胱氨酸（NAC）对5xFAD小鼠氧化应激、脑Aβ水平、屏障渗漏、肾功能和认知的影响。8周龄的5xFAD小鼠喂食补充有600 mg/kg NAC的啮齿动物饮食4周；野生型（WT）小鼠和对照5xFAD小鼠喂食常规啮齿动物饮食。与WT对照相比，我们检测到未经治疗的5xFAD小鼠脑和肾中4-羟基壬烯醛（4-HNE）水平升高、肌酐清除率降低以及血浆S100β水平升高。与WT相比，未经治疗的5xFAD小鼠还具有更高的毛细血管渗漏、降低的P-糖蛋白活性和受损的认知能力。用NAC治疗5xFAD小鼠可降低脑Aβ40水平，将4-HNE水平恢复至对照水平，改善肌酐清除率，减少毛细血管渗漏，并降低血浆S100β水平。如Y迷宫所示，NAC改善了5xFAD小鼠的认知表现。我们的研究结果表明，Aβ诱导的氧化应激导致5xFAD小鼠的屏障功能障碍、肾功能损害和认知缺陷。值得注意的是，NAC治疗减轻了这些影响，表明其通过降低氧化应激作为AD和其他Aβ相关病症辅助治疗的潜力。
