Serotonin and Amyloidopathy

描述（由申请人提供）：淀粉样蛋白病是几种痴呆症的重要特征-阿尔茨海默病（AD）、路易体痴呆（DLB）和帕金森病痴呆（PDD）。淀粉样蛋白（Ab）肽的产生是重要的治疗靶点。体外实验和鼠遗传模型实验表明，Ab肽的产生通过一些G蛋白偶联受体（包括5-羟色胺受体）的活化而减少。适度的人类数据支持这些有趣的观察。基于初步研究，我们的中心假设是，胆碱能神经传递抑制Ab淀粉样蛋白的产生-沉积。这一假说的一个重要推论是，减少区域胆碱能神经支配应与抗体沉积呈负相关。帕金森病（PD）-一种以肾上腺素能投射系统的可变变性和可变Ab肽沉积为特征的疾病-提供了一个模型来评估这一推论预测。在PD受试者的初步PET成像研究中，我们发现区域前脑肾上腺素能神经支配和Ab沉积之间存在很强的负相关性，分别用5-羟色胺转运蛋白配体[11 C]DASB和淀粉样蛋白配体[11 C]PiB测量。这些有趣的数据受到样本量相对较小和横断面研究设计的限制。我们建议对PD受试者进行更大规模的纵向研究，以更具体地评估肾上腺素能系统变化与脑Ab淀粉样蛋白沉积之间的相互作用。为了确定局部肾上腺素能神经支配和Ab淀粉样蛋白沉积之间的关系是否具有普遍性，我们将在无认知症状的老年对照样本中进行平行横断面研究。验证我们的预测将有力地支持在PD和其他痴呆症前的临床研究的实施，目的是使用胆碱能药物来修改大脑Ab肽产生-沉积的自然史。我们预测的错误同样有价值，因为它会破坏中心假设，并阻止将肾上腺素能药物作为MCI、AD、DLB和PD的疾病调节剂的临床试验的实施。

DESCRIPTION (provided by applicant): Amyloidopathy is an important feature of several dementias - Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Amyloid (Ab) peptide production is an important therapeutic target. Experimental in vitro and murine genetic model experiments indicate that Ab peptide production is reduced by activation of some G-protein coupled receptors, including serotonin receptors. Modest human data supports these interesting observations. Based on preliminary studies, our central hypothesis is that serotoninergic neurotransmission inhibits Ab amyloid production-deposition. An important corollary of this hypothesis is that diminished regional serotoninergic innervation should correlate inversely with Ab deposition. Parkinson disease (PD) - a disorder characterized by variable degeneration of serotoninergic projection systems and variable Ab peptide deposition - provides a model to evaluate this corollary prediction. In preliminary PET imaging studies of PD subjects, we found a strong inverse correlation between regional forebrain serotoninergic innervation and Ab deposition as measured with the serotonin transporter ligand [11C]DASB and the amyloid ligand [11C]PiB, respectively. These intriguing data are limited by relatively small sample size and cross-sectional study design. We propose a larger longitudinal study of PD subjects that will yield more specific assessments of the interactions between serotoninergic system changes and brain Ab amyloid deposition. To determine if the relationship between regional serotoninergic innervation and Ab amyloid deposition is generalizable, we will perform a parallel cross-sectional study in a sample of cognitively asymptomatic elderly controls. Validation of our predictions will strongly support the implementation of clinical investigations in PD and other pre-dementias aimed at using serotoninergic agents to modify the natural history of cerebral Ab peptide production-deposition. Falsification of our predictions will be equally valuable as it would undermine the central hypothesis and forestall the implementation of clinical trials of serotoninergic agents as disease modifying agents in MCI, AD, DLB, and PD.