Majid Tabassum, Griffin Deric, Criss Zachary, Jarpe Matthew, Pautler Robia G
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
Acetylon Pharmaceuticals, Boston, MA, USA.
Alzheimers Dement (N Y). 2015 Oct 11;1(3):170-181. doi: 10.1016/j.trci.2015.08.001. eCollection 2015 Nov.
Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmortem tissue samples from patients. However, HDAC6 inhibitors have had limited success preclinically due to low blood-brain barrier penetration.
We investigated a specific, potent HDAC6 inhibitor (ACY-738) in a mouse model of AD. We determined the effects of ACY-738 treatment on axonal transport, behavior, and pathology in amyloid precursor protein/presenilin 1 mice.
We demonstrated improvements in in vivo axonal transport in two treatment groups as a result of ACY-738 brain levels. We also demonstrated recovery of short-term learning and memory deficits, hyperactivity, and modifications of tau and tubulin.
Our findings implicate specific, targeted HDAC6 inhibitors as potential therapeutics and demonstrate that further investigations are warranted into effects of HDAC6 inhibitors in AD.
目前针对阿尔茨海默病（AD）的治疗主要集中在延缓疾病进展，这表明需要更有效的治疗靶点。组蛋白去乙酰化酶6（HDAC6）调节微管蛋白乙酰化，被认为是一个有吸引力的靶点。在AD患者的尸检组织样本中，HDAC6也有所升高。然而，由于血脑屏障穿透率低，HDAC6抑制剂在临床前研究中取得的成功有限。
我们在AD小鼠模型中研究了一种特异性、强效的HDAC6抑制剂（ACY-738）。我们确定了ACY-738治疗对淀粉样前体蛋白/早老素1小鼠轴突运输、行为和病理学的影响。
我们证明，由于ACY-738在脑中的水平，两个治疗组的体内轴突运输得到改善。我们还证明了短期学习和记忆缺陷、多动以及tau蛋白和微管蛋白修饰的恢复。
我们的研究结果表明，特异性、靶向性HDAC6抑制剂具有潜在的治疗作用，并证明有必要进一步研究HDAC6抑制剂在AD中的作用。
