PI Pharmacy Information 2160-441X Scientific Research Publishing 10.12677/PI.2017.62006 PI-20517 PI20170200000_62573314.pdf 医药卫生 脑源性神经营养因子在阿尔茨海默症中作用研究进展 Research Progress of Brain-Derived Neurotrophic Factor in Alzheimer’s Disease 冯 晓文 2 1 何 玲 2 * 中国药科大学，江苏 南京 null * E-mail: 1178470617@qq.com(何玲) ; 03 05 2017 06 02 31 35 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

阿尔茨海默症(AD)是引起老年痴呆的主要原因，其病理特征包括淀粉样斑块和神经纤维缠结。AD广泛的神经元和突触丢失引起记忆和认知功能进行性减退。脑源性神经营养因子(BDNF)是成人大脑内分布最广泛的神经营养因子。BDNF在记忆获得和巩固的细胞生物学基础突触发生及突触可塑性中发挥关键作用。研究表明，BDNF可能成为AD的生物标记和治疗靶标。本文主要对BDNF在AD中发挥的作用及其治疗策略进行综述。 Alzheimer’s disease (AD) is one of the most common causes of dementia in the elderly. It is char-acterized by the accumulation of Aβ plaques and neurofibrillary tangles, which are accompanied by widespread neuronal and synaptic loss, causing progressive loss of memory and cognitive function. Brain-derived neurotrophic factor (BDNF) is the most widely distributed NTs in adult brain and is a key molecule in the maintenance of synaptic plasticity and synaptogenesis, which is the cellular biological basis of memory acquisition and consolidation. BDNF may play a potential role in the pathogenesis of Alzheimer’s disease. The review provides the role and therapeutic strategy of brain-derived neurotrophic factor in Alzheimer’s disease in major.

阿尔茨海默症，脑源性神经营养因子，发病机制，治疗策略, Alzheimer’s Disease Brain-Derived Neurotrophic Factor Pathogenesis Therapeutic Strategy 脑源性神经营养因子在阿尔茨海默症中 作用研究进展<sup> </sup>

冯晓文，何玲*

中国药科大学，江苏 南京

收稿日期：2017年4月23日；录用日期：2017年5月13日；发布日期：2017年5月16日

 摘 要

阿尔茨海默症(AD)是引起老年痴呆的主要原因，其病理特征包括淀粉样斑块和神经纤维缠结。AD广泛的神经元和突触丢失引起记忆和认知功能进行性减退。脑源性神经营养因子(BDNF)是成人大脑内分布最广泛的神经营养因子。BDNF在记忆获得和巩固的细胞生物学基础突触发生及突触可塑性中发挥关键作用。研究表明，BDNF可能成为AD的生物标记和治疗靶标。本文主要对BDNF在AD中发挥的作用及其治疗策略进行综述。

关键词 :阿尔茨海默症，脑源性神经营养因子，发病机制，治疗策略

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This work is licensed under the Creative Commons Attribution International License (CC BY).

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 1. 引言

阿尔茨海默症(AD)是痴呆中最常见的类型，在所有痴呆患者中占到50%至75%，超过1/3的老年人受其所累 [ 1 ] 。并且，随着年龄的增长，每5年患病风险增加一倍。阿尔茨海默病协会把AD定义为一种引起记忆、认知和行为障碍的不可逆的进行性致命脑病。随着人类寿命的延长，预测未来25年罹患阿尔茨海默症的人数将增加40%左右，同时伴随增长的还有用于AD治疗和护理的费用 [ 2 ] 。AD的病理特征包括β-淀粉样蛋白(Aβ)沉积和tau蛋白高度磷酸化的神经纤维缠结，伴随广泛的神经元和突触丢失，突触发生和突触可塑性障碍。脑源性神经营养因子(BDNF)是神经营养因子家族(NTs)成员，在哺乳动物脑内分布最为广泛。BDNF水平及其表达在AD患者血液和中枢神经系统持续下降。BDNF通过激活高亲和力受体TrkB和低亲和力受体p75NTR调节神经元存活、分化和可塑性 [ 3 ] 。研究表明，通过TrkB减少BDNF信号可导致空间记忆受损 [ 4 ] ，而TrkB表达适度增加可增强记忆 [ 5 ] 。BDNF可能在AD发病机制和治疗中发挥潜在作用。

 2. BDNF与AD发病机制的关系 2.1. BDNF与Aβ、tau

β-淀粉样蛋白(Aβ)、tau蛋白高度磷酸化的神经纤维缠结(NTF)是诱发AD的主要原因。AD患者Aβ、NTF沉积的部位在皮层、海马、基底前脑和杏仁核等脑区 [ 6 ] 。BDNF对学习记忆具有重要作用，在海马、皮层和基底前脑等脑区较为活跃 [ 7 ] 。BDNF与Aβ、p-tau具有相似的分布区域，提示BDNF在AD的两大病理进程中发挥保护作用。

Aβ的异常沉积引起BDNF水平降低，随之诱发Aβ相关的AD神经毒性 [ 8 ] ，而BDNF水平的降低不会诱发Aβ沉积 [ 9 ] 。Aβ作用于Ras-MAPK/ERK通道和PI3K-Akt信号通路，减少活化调节细胞骨架相关蛋白(Arc)的表达 [ 10 ] ，抑制转录因子CREB结合到BDNF的启动区域，最终导致神经元BDNF转录抑制 [ 11 ] 。Aβ作用于BDNF高亲和力受体TrkB，降低BDNF/TrkB水平，损伤TrkB相关信号通路，导致AD脑内神经元存活减少 [ 12 ] 。Aβ损伤神经元轴突，诱导微观结构变化，导致细胞内BDNF运输障碍 [ 13 ] 。BDNF增加APP启动子转录，通过APP的α-分泌酶剪切途径，形成可溶性APP和AICD [ 14 ] 。BDNF修复Aβ诱导的神经毒性，显著增加突触可塑性。

Tau蛋白高度磷酸化形成NTF，导致神经毒性。Tau蛋白过度磷酸化与催化tau蛋白磷酸化的激酶和催化tau蛋白去磷酸化的蛋白磷酸酶有关。BDNF作用于最重要的tau蛋白激酶GSK-3β，抑制GSK-3β磷酸化，从而抑制tau蛋白磷酸化 [ 15 ] 。BDNF/TrkB通路激活可引起tau蛋白去磷酸化，反之TrkB失活则tau蛋白去磷酸化减少。研究表明，BDNF可通过TrkB受体激活PI3K-Akt通路，作用于tau蛋白去磷酸化位点AT8，引起tau蛋白去磷酸化 [ 15 ] 。

 2.2. BDNF与突触修复

突触丢失和突触功能障碍与神经退行性疾病的恶化密切相关。在AD大脑中，特别是海马、额叶皮层、顶叶皮层和内嗅皮层等脑区，突触进行性丢失 [ 16 ] 。Selkoe认为，AD是突触障碍 [ 17 ] 。在AD的病理进程中，Aβ诱导的轻微突触退化要早于神经元退化 [ 17 ] 。在突触相关的所有生物分子中，BDNF是目前研究最深入，并且是唯一得到论证与人类突触功能调节密切相关的分子 [ 18 ] 。在成人大脑中，BDNF的主要功能是突触修复，包括增加突触传递、易化突触可塑性和促进突触生长。体内外实验表明，应用外源性BDNF或增加内源性BDNF水平可以反转Aβ诱导的LTP和突触传递障碍 [ 19 ] 。BDNF诱导NMDA受体和AMPA受体的自磷酸化，增强CaMKII的功能，起到突触保护作用 [ 20 ] 。

 3. BDNF相关AD治疗

BDNF本身由于血浆半衰期短、血脑屏障(BBB)渗透性差等药动学特点没有合适的给药途径。针对BDNF的AD治疗策略主要包括增加内源性BDNF及其受体TrkB的表达、靶向BDNF治疗和非特异性治疗。

经典抗AD药物，胆碱酯酶抑制剂多奈哌齐、加兰他敏可增加CREB和Akt磷酸化，活化受到AD抑制的下游通路Akt/CREB/BDNF-TrkB，增加BDNF及其受体的表达 [ 21 ] 。NMDA受体拮抗剂美金刚在临床上用于治疗重度AD，已证实可通过活化Akt/CREB/BDNF-TrkB通路增加BDNF表达 [ 22 ] 。正在进行新药临床试验的新型次黄嘌呤衍生物Neotrofin(AIT082)可增加BDNF的表达。Neotrofin刺激轴突生长、增加BDNF合成、增强记忆。在临床前和临床试验中，Neotrofin具有口服给药稳定性好、剂量范围宽和BBB渗透性强等优势 [ 23 ] 。天然药物姜黄素可通过PI3K/Akt/GSK-3β信号通路，上调BDNF水平缓解Aβ诱导的认知损伤 [ 24 ] 。

BDNF慢病毒基因导入内嗅皮层可增加APP转基因小鼠海马BDNF水平，增加皮层神经元数目，提高突触小泡蛋白免疫反应性，改善海马相关记忆 [ 25 ] 。小分子BDNF拟肽具有更适宜的药动学特点。BDNF拟肽7,8-二羟基黄酮水合物(7,8-DHF)是TrkB的高特异性激动剂，与BDNF具有相似的效应，可缓解Aβ诱导的神经毒性和突触功能障碍 [ 26 ] 。向APP/PS1/tau转基因小鼠海马中移植神经干细胞可增加其空间学习能力，而植入BDNF表达失活的神经干细胞没有这种作用，说明其增加空间学习能力的作用与BDNF相关 [ 27 ] 。BDNF调节肽，腹腔注射三肽Neuropep-1可增加APP/PS1/tau转基因小鼠脑内BDNF水平，增加其空间学习记忆能力，减少脑内淀粉样斑块的负荷 [ 28 ] 。

社交活动可增加APP/PS1双转小鼠海马BDNF水平，增强海马神经发生，改善空间记忆 [ 29 ] 。体育锻炼可增加实验动物循环系统BDNF水平。有氧运动增加AD患者血清BDNF水平，血清BDNF水平与海马体积和空间记忆能力密切相关 [ 30 ] 。

 4. 展望

关于BDNF的研究近十年有了很大进展。BDNF不仅对外周和中枢神经系统神经元的生长、分化、成熟、存活有重要作用，而且与成年中枢神经系统突触可塑性、神经传递、受体敏感性调节密切相关，参与神经退行性疾病AD的发病和病理生理过程，可能成为AD的生物标记和治疗靶标。BDNF扩散速率小、体内半衰期短和血脑屏障渗透性低的药动学特点，限制其在AD治疗中的应用。今后人们关注BDNF在AD中的作用，尝试干细胞移植、BDNF基因传送递、拟态BDNF、发现新型小分子物质等方法，改善BDNF及其受体的表达，为AD患者提供新的治疗策略。

 基金项目

国家自然科学基金(81673434)。

 文章引用

冯晓文,何 玲. 脑源性神经营养因子在阿尔茨海默症中作用研究进展Research Progress of Brain-Derived Neurotrophic Factor in Alzheimer’s Disease[J]. 药物资讯, 2017, 06(02): 31-35. http://dx.doi.org/10.12677/PI.2017.62006

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