Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer Disease

使用γ-分泌酶调节剂治疗以预防唐氏综合症和阿尔茨海默病小鼠模型的神经退行性变

• 批准号: 10338158
• 负责人: William C Mobley
• 金额: $ 51.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338158
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-42; Amyloid beta-Protein Precursor; Atrophic; Autopsy; Behavior; Biochemistry; Blinded; Body Weight; Brain; C-terminal; Canis familiaris; Characteristics; Clinical Trials Design; Cognition; Cognitive; Complex; Data; Data Analyses; Defect; Dementia; Dose; Down Syndrome; Early Endosome; Endosomes; Evaluation; Event; Female; Functional disorder; Future; G-substrate; GTP-Binding Protein alpha Subunits, Gs; Gene Proteins; Genes; Genetic; Grant; Guanosine Triphosphate Phosphohydrolases; Human Amyloid Precursor Protein; In Vitro; Intercept; Length; Link; Measures; Mediating; Modeling; Morphology; Mus; Nerve Degeneration; Neurons; Outcome; Pathogenesis; Phenotype; Population; Proteins; RTN4 gene; Regulation; Rodent; Senile Plaques; Signal Transduction; Structure; Synapses; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; age related; age related neurodegeneration; amyloid precursor protein processing; basal forebrain; base; cerebral amyloidosis; cholinergic; disease phenotype; entorhinal cortex; gamma secretase; genotoxicity; improved; in vivo; inhibitor; locus ceruleus structure; male; mouse model; mutant; neurodegenerative phenotype; neuropathology; neurotrophic factor; nonhuman primate; prevent; small molecule; tau Proteins; tau phosphorylation; tau-1; therapeutic evaluation; trafficking

We aim to prevent Alzheimer disease (AD) in adults with DS (trisomy 21), referred to as AD in DS (AD-DS) by enhancing processing of the amyloid precursor protein (APP) to reduce the levels of the C-terminal 99 residue fragment (C99) and Aβ42. The therapeutic premise is based on: 1) increased APP gene dose is necessary for AD-DS, a finding replicated in mouse models of DS. By normalizing APP dose in DS models we eliminated: a) age-related degeneration of neurons in locus coeruleus (LCNs) and basal forebrain complex (BFCNs), b) hyper- phosphorylation of Tau, and c) enlargement of early endosomes; 2) increased C99 and Aβ42 acted via increased activation of Rab5 to induce changes in endosomes resulting in reduced trafficking of neurotrophic signals and BFCN atrophy. The evidence suggests that increased C99 and Aβ42 cause degeneration via deficits in endosomal trafficking of neurotrophic signals and motivates treatments to reduce C99 and Aβ42. Because both are substrates for γ-secretase, increasing γ-secretase activity should decrease levels and prevent or mitigate endosomal and degenerative phenotypes. BPN15606, a γ-secretase modulator (GSM), increases γ-secretase activity. In vitro, BPN15606 potently reduced C99 and Aβ42, reduced Rab5 activation and restored endosome size and trafficking of neurotrophins. In vivo, it reversed endosomal enlargement, improved LCN number, reversed Tau hyper-phosphorylation and enhanced cognition. In mouse models of AD-DS and AD/cerebral amyloidosis we will test the therapeutic hypothesis that BPN15606 will reduce the levels of C99 and Aβ42 to prevent and/or lessen neurodegeneration. The mechanistic hypothesis tested is that BPN15606 will normalize endosomal structure and function, neurotrophin signaling and trafficking, and improve cognition. Extensive pharm/tox studies qualify BPN15606 for our studies. Specific Aims: 1. To detail the time of onset of neurodegeneration in mouse models of AD-DS and AD/cerebral amyloidosis. Studies of the Dp16 model of AD-DS and Line 41 model of AD will be submitted to unbiased stereological studies of morphology and biochemistry, to quantitatively define onset of degeneration of neurons and synapses (Dp16: LCNs, BFCNs; Line 41: BFCNs, CA3), emergence of p-Tau and amyloid plaques. 2. To examine the effect of BPN15606 treatment before and after onset of neurodegeneration in the AD-DS model. Dp16 and 2N mice will be treated with an effective, safe dose of BPN15606. Guided by quantitative GO/NOGO criteria, the extent to which enhanced APP processing results in lessening of degenerative, endosomal and cognitive phenotypes will be assessed. 3. To examine the effect of BPN15606 treatment before and after onset of neurodegeneration in the AD/cerebral amyloidosis model. The same approach will guide BPN15606 studies in the Line 41 mouse. BPN15606-mediated reductions in degeneration will support the therapeutic hypothesis; normalization of endosomal and cognitive phenotypes will support the mechanistic hypothesis. These studies are intended to inform and guide trials of BPN15606 in AD-DS.

我们的目标是预防患有 DS（21 三体）的成人阿尔茨海默病 (AD)（称为 DS 中的 AD (AD-DS)） 增强淀粉样前体蛋白 (APP) 的加工以降低 C 端 99 残基的水平 片段（C99）和Aβ42的治疗前提基于：1）增加APP基因剂量是必要的。 AD-DS，在 DS 小鼠模型中复制的发现 通过标准化 DS 模型中的 APP 剂量，我们消除了：a) 蓝斑 (LCN) 和基底前脑复合体 (BFCN) 中神经元的年龄相关性变性，b) 过度 Tau 磷酸化，c) 早期内体增大；2) C99 和 Aβ42 增加通过增加起作用 Rab5 的激活诱导内体发生变化，导致神经营养信号的运输减少 BFCN 萎缩的证据表明，C99 和 Aβ42 的增加会通过缺乏而导致退化。 神经营养信号的内体运输和减少 C99 和 Aβ42 的动机治疗。 是 γ-分泌酶的底物，增加 γ-分泌酶活性应降低水平并预防或减轻 BPN15606 是一种 γ-分泌酶调节剂 (GSM)，可增加 γ-分泌酶。 在体外，BPN15606 有效降低 C99 和 Aβ42，减少 Rab5 激活并恢复内体。 在体内，它逆转了内体的增大，提高了 LCN 的数量。 在 AD-DS 和 AD/大脑小鼠模型中逆转 Tau 过度磷酸化并增强认知。 淀粉样变性，我们将测试 BPN15606 会降低 C99 和 Aβ42 水平的治疗假设 测试的机制假设是 BPN15606 会预防和/或减轻神经变性。 使内体结构和功能、神经营养蛋白信号传导和运输正常化，并改善 广泛的药物/毒性研究使 BPN15606 符合我们的研究具体目标： 1. 详细说明时间。 AD-DS 和 AD/脑淀粉样变性小鼠模型中神经变性的发生 Dp16 模型的研究。 AD-DS 的 AD-DS 和 AD 的 Line 41 模型将提交给形态学和 生物化学，定量定义神经元和突触退化的开始（Dp16：LCN、BFCN；Line 41：BFCN、CA3)、p-Tau 和淀粉样斑块的出现 2. 检查 BPN15606 治疗的效果。 Dp16 和 2N 小鼠神经变性发作之前和之后将接受 BPN15606 的有效、安全剂量以定量 GO/NOGO 标准为指导，增强 APP 的程度。 3. 将评估减少退行性、内体和认知表型的处理结果。 检查 AD/脑神经变性发作前后 BPN15606 治疗的效果 相同的方法将指导 BPN15606 介导的 BPN15606 小鼠研究。 变性的减少将支持内体和认知正常化的治疗假设； 表型将支持机制假说，旨在为试验提供信息和指导。 AD-DS 中的 BPN15606。