Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment
Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment
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DOI：
10.1038/mp.2015.74
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发表时间：
2015-10-01
影响因子：
11
通讯作者：
Rominger, A.
中科院分区：
文献类型：
--
作者：
Brendel, M.;Jaworska, A.;Rominger, A.
在一项使用β -淀粉样蛋白（a β）示踪剂[F-18]-florbetaben的正电子发射断层扫描（PET）研究中，我们之前发现，a β在表达瑞典突变体APP （APP- swe）的转基因小鼠体内的沉积可以被追踪。分泌酶调节剂（gsm）是一种很有前途的治疗药物，它可以减少易于聚集的A β(42)的产生，而不会阻断一般的。分泌酶的活动。我们现在的目的是研究一种新型的GSM[8-（4-氟苯基）-[1,2,4]三唑[1,5-a]吡啶-2-基]-[1-（3-甲基-[1,2,4]噻二唑-5-基）-哌啶-4-基]胺（RO5506284）在体外和体内对淀粉样斑块负荷的影响，并使用纵向a β -微pet追踪个体动物。将12月龄雌性转基因（TG） APP-Swe小鼠分为对照组（TG- veh, n = 12）和治疗组（TG- gsm, n = 12），治疗组每天给予RO5506284 （30 mg kg(-1)）治疗，持续6个月。在基线（12个月）、随访1（16个月）和随访2（18个月，终止扫描）共获得131份A β - pet记录，并对A β进行组织学和生化分析。我们将PET数据作为基于voi的皮质标准摄取值比（SUVR）进行分析，以小脑作为参考区域。在RO5506284治疗的6个月期间，TG-GSM组通过PET评估的个体斑块负荷几乎保持不变，而TG-VEH组则逐渐增加。TG-GSM小鼠的基线SUVR与δ %-SUVR相关，表明个体反应预测。相对于单个基线斑块负荷估计，TG-GSM组与TG-VEH组的不溶性A β(42)减少56%。此外，斑块大小直方图显示TG小鼠组之间的分布不同，TG- gsm动物的小斑块较少。综上所述，在第一项A - pet研究中，我们在AD小鼠模型中监测了用强效GSM延长治疗的情况，发现新生淀粉样蛋白发生明显减弱。此外，纵向PET允许对单个斑块负荷动力学进行无创评估，从而适应动物间的差异。
In a positron-emission tomography (PET) study with the beta-amyloid (A beta) tracer [F-18]-florbetaben, we previously showed that A beta deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. gamma-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone A beta(42) species without blocking general.-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4] triazolo[1,5-a] pyridin-2-yl]-[1-(3-methyl-[1,2,4] thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal A beta-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n = 12) and treatment groups (TG-GSM, n = 12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 A beta-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of A beta were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Delta%-SUVR, indicating individual response prediction. Insoluble A beta(42) was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first A beta-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.