Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines, Dallas, TX, 75390, USA.
Alzheimers Res Ther. 2023 Oct 17;15(1):179. doi: 10.1186/s13195-023-01323-5.
Current treatments for Alzheimer's disease (AD) have largely failed to yield significant therapeutic benefits. Novel approaches are desperately needed to help address this immense public health issue. Data suggests that early intervention at the first stages of mild cognitive impairment may have a greater chance for success. The calcineurin (CN)-Pin1 signaling cascade can be selectively targeted with tacrolimus (FK506), a highly specific, FDA-approved CN inhibitor used safely for > 20 years in solid organ transplant recipients. AD prevalence was significantly reduced in solid organ recipients treated with FK506.
Time release pellets were used to deliver constant FK506 dosage to APP/PS1 mice without deleterious manipulation or handling. Immunofluorescence, histology, molecular biology, and behavior were used to evaluate changes in AD pathology.
FK506 can be safely and consistently delivered into juvenile APP/PS1 mice via time-release pellets to levels roughly seen in transplant patients, leading to the normalization of CN activity and reduction or elimination of AD pathologies including synapse loss, neuroinflammation, and cognitive impairment. Pin1 activity and function were rescued despite the continuing presence of high levels of transgenic Aβ. Indicators of neuroinflammation including Iba1 positivity and IL-6 production were also reduced to normal levels. Peripheral blood mononuclear cells (PBMC) obtained during treatment or splenocytes isolated at euthanasia activated normally after mitogens.
Low-dose, constant FK506 can normalize CNS CN and Pin1 activity, suppress neuroinflammation, and attenuate AD-associated pathology without blocking peripheral IL-2 responses making repurposed FK506 a viable option for early, therapeutic intervention in AD.
目前治疗阿尔茨海默病（AD）的方法在很大程度上未能产生显著的治疗效果。急需新的方法来帮助解决这一巨大的公共卫生问题。有数据表明，在轻度认知障碍的早期阶段进行早期干预可能会有更大的成功机会。钙调神经磷酸酶（CN）-Pin1 信号级联可以用他克莫司（FK506）特异性靶向，FK506 是一种高度特异性的、已获 FDA 批准的 CN 抑制剂，已在实体器官移植受者中安全使用超过 20 年。FK506 治疗的实体器官受者 AD 患病率显著降低。
使用缓释微球向 APP/PS1 小鼠持续释放 FK506 剂量，而不会造成有害的操作或处理。免疫荧光、组织学、分子生物学和行为学用于评估 AD 病理变化。
FK506 可以通过缓释微球安全且持续地递送至幼年 APP/PS1 小鼠，达到移植患者的大致水平，从而使 CN 活性正常化，并减少或消除 AD 病理，包括突触丢失、神经炎症和认知障碍。尽管持续存在高水平的转基因 Aβ，Pin1 活性和功能仍得到挽救。神经炎症标志物包括 Iba1 阳性和 IL-6 产生也降低到正常水平。在治疗期间获得的外周血单核细胞（PBMC）或安乐死时分离的脾细胞在有丝分裂原激活后正常激活。
低剂量、持续的 FK506 可以使中枢神经系统 CN 和 Pin1 活性正常化，抑制神经炎症，并减轻 AD 相关病理，而不阻断外周 IL-2 反应，使再利用 FK506 成为 AD 早期治疗的可行选择。
