Instituto de Investigaciones Bioquímicas de Bahía Blanca, B8000FWB, Bahía Blanca, Argentina.
CNS Drugs. 2014 Nov;28(11):975-87. doi: 10.1007/s40263-014-0201-3.
Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the α7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-β-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the α7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target α7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, α7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors.
阿尔茨海默病（AD）是老年人中最常见的痴呆症形式。该疾病的特征性标志包括淀粉样老年斑的形成和神经原纤维缠结的沉积。这些变化发生在 AD 的临床表现（尤其是认知障碍）明显之前很久。烟碱型乙酰胆碱受体（AChRs），特别是α7 亚型，在与认知和记忆功能相关的大脑区域中高度表达，并参与感觉信息的处理。有强有力的证据表明 AChRs 参与了 AD。本综述简要介绍了当前针对病理生理发现（淀粉样β肽斑块、神经原纤维缠结）的策略，然后重点介绍了 AD 中最近的药物干预努力，特别是针对α7 AChR 的药物干预。尽管胆碱酯酶抑制剂（如多奈哌齐、加兰他敏或利伐斯的明）与非竞争性 N-甲基-D-天冬氨酸受体拮抗剂美金刚一起，处于 AD 目前临床干预的前沿，但 AChR 分子药理学的新见解正在将其他针对 AChR 的药物推向舞台中心。其中包括选择性靶向α7 AChR 的正变构调节剂，旨在释放阻碍激动剂介导的α7 AChR 通道激活的因素。这需要更详细地了解 AChR 在各种信号级联中的分布、功能特性和参与情况，以及所有这些特性的相应异常，以便能够在药物设计中制定策略，并评估针对这类神经递质受体的新化合物的治疗可能性。
