Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.
Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.
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2001
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通讯作者：
K. Dineley;M. Westerman;D. Bui;K. Bell;K. Ashe;J. Sweatt
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作者：
K. Dineley;M. Westerman;D. Bui;K. Bell;K. Ashe;J. Sweatt
阿尔茨海默病(AD)是最常见的老年性痴呆，其患病率正在迅速上升，预计到2025年全球将有1400万人受到影响。阿尔茨海默病学习和记忆障碍背后的信号转导机制还知之甚少。AD患者脑组织中的β-淀粉样多肽(Abeta)升高，是淀粉样斑块的主要成分，是死后诊断疾病的主要标准。使用急性和器官型的海马片制备，我们证明了Abeta42(Abeta42)通过α7烟碱型乙酰胆碱受体(NAChRs)与丝裂原活化蛋白激酶(MAPK)级联。在体内，Abeta的升高，如在AD动物模型中所展示的那样，导致α7nAChR蛋白的上调。老年动物海马区α7nAChR表达上调的同时，细胞外信号调节激酶(ERK2)42 kDa亚型MAPK表达下调。长时程增强的转录介质和ERK MAPK级联的下游靶蛋白cAMP调节元件结合蛋白(CREB)的磷酸化状态也受到影响。这些发现支持这样的模型，即AD时海马区信号转导通路的紊乱是由于Abeta负荷增加和ERK MAPK通路以α7nAChR依赖的方式慢性激活，最终导致ERK2 MAPK下调和CREB蛋白磷酸化降低所致。
Alzheimer's Disease (AD) is the most common of the senile dementias, the prevalence of which is increasing rapidly, with a projected 14 million affected worldwide by 2025. The signal transduction mechanisms that underlie the learning and memory derangements in AD are poorly understood. beta-Amyloid (Abeta) peptides are elevated in brain tissue of AD patients and are the principal component of amyloid plaques, a major criterion for postmortem diagnosis of the disease. Using acute and organotypic hippocampal slice preparations, we demonstrate that Abeta peptide 1-42 (Abeta42) couples to the mitogen-activated protein kinase (MAPK) cascade via alpha7 nicotinic acetylcholine receptors (nAChRs). In vivo elevation of Abeta, such as that exhibited in an animal model for AD, leads to the upregulation of alpha7 nAChR protein. alpha7 nAChR upregulation occurs concomitantly with the downregulation of the 42 kDa isoform of extracellular signal-regulated kinase (ERK2) MAPK in hippocampi of aged animals. The phosphorylation state of a transcriptional mediator of long-term potentiation and a downstream target of the ERK MAPK cascade, the cAMP-regulatory element binding (CREB) protein, were affected also. These findings support the model that derangement of hippocampus signal transduction cascades in AD arises as a consequence of increased Abeta burden and chronic activation of the ERK MAPK cascade in an alpha7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.