Department of Anatomy and Cell Biology, College of Medicine, 808 S Wood St. M/C 512, University of Illinois at Chicago, Chicago, IL 60612, USA.
Exp Neurol. 2010 Jun;223(2):267-81. doi: 10.1016/j.expneurol.2009.08.009. Epub 2009 Aug 19.
While a massive and progressive neuronal loss in specific areas such as the hippocampus and cortex unequivocally underlies cognitive deterioration and memory loss in Alzheimer's disease, noteworthy alterations take place in the neurogenic microenvironments, namely, the subgranule layer of the dentate gyrus and the subventricular zone. Compromised neurogenesis presumably takes place earlier than onset of hallmark lesions or neuronal loss, and may play a role in the initiation and progression of neuropathology in Alzheimer's disease. Neurogenesis in the adult brain is thought to play a role in numerous forms and aspects of learning and memory and contribute to the plasticity of the hippocampus and olfactory system. Misregulated or impaired neurogenesis on the other hand, may compromise plasticity and neuronal function in these areas and exacerbate neuronal vulnerability. Interestingly, increasing evidence suggests that molecular players in Alzheimer's disease, including PS1, APP and its metabolites, play a role in adult neurogenesis. In addition, recent studies suggest that alterations in tau phosphorylation are pronounced in neurogenic areas, and may interfere with the potential central role of tau proteins in neuronal maturation and differentiation. On the other hand, numerous neurogenic players, such as Notch-1, ErbB4 and L1 are substrates of alpha- beta- and gamma- secretase that play a major role in Alzheimer's disease. This review will discuss current knowledge concerning alterations of neurogenesis in Alzheimer's disease with specific emphasis on the cross-talk between signaling molecules involved in both processes, and the ways by which familial Alzheimer's disease-linked dysfunction of these signaling molecules affect neurogenesis in the adult brain.
虽然特定区域（如海马体和皮质）中大量且渐进的神经元丧失明确导致了阿尔茨海默病的认知恶化和记忆丧失，但神经发生的微环境（即齿状回颗粒下层和侧脑室下区）也发生了显著改变。神经发生的损伤可能发生在标志性病变或神经元丧失之前，并且可能在阿尔茨海默病的神经病理学的发生和进展中发挥作用。成人脑内的神经发生被认为在学习和记忆的多种形式和方面发挥作用，并有助于海马体和嗅觉系统的可塑性。另一方面，失调或受损的神经发生可能会损害这些区域的可塑性和神经元功能，并使神经元易损性恶化。有趣的是，越来越多的证据表明，阿尔茨海默病中的分子参与者，包括 PS1、APP 及其代谢物，在成人神经发生中发挥作用。此外，最近的研究表明，神经发生区域中的 tau 磷酸化改变明显，并且可能干扰 tau 蛋白在神经元成熟和分化中的潜在核心作用。另一方面，许多神经发生因子，如 Notch-1、ErbB4 和 L1，是在阿尔茨海默病中起主要作用的α-β-和γ-分泌酶的底物。这篇综述将讨论阿尔茨海默病中神经发生改变的最新知识，特别强调这两个过程中涉及的信号分子之间的串扰，以及这些信号分子的家族性阿尔茨海默病相关功能障碍如何影响成人脑内的神经发生。
