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）的成人中的阿尔茨海默病（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-末端99残基的水平 片段（C99）和Aβ42。治疗的前提是基于：1）增加APP基因剂量是必要的， AD-DS，在DS小鼠模型中重复的发现。通过在DS模型中标准化APP剂量，我们排除了： 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）超- c）早期内体增大; 2）C99和Aβ42的增加通过增加 激活Rab 5以诱导内体的变化，导致神经营养信号的运输减少， BFCN萎缩。有证据表明，C99和Aβ42的增加会通过缺乏细胞因子而导致变性。 内体运输神经营养信号，并促使治疗减少C99和Aβ42。因为两 是γ-分泌酶的底物，增加γ-分泌酶活性应降低水平并防止或减轻 内体和退化表型。BPN 15606是一种γ-分泌酶调节剂（GSM）， 活动在体外，BPN 15606有效地减少C99和Aβ42，减少Rab 5活化并恢复内体 神经营养素的大小和运输。在体内，它逆转了内体增大，提高了LCN数， 逆转Tau蛋白过度磷酸化并增强认知能力。在AD-DS和AD/脑的小鼠模型中 我们将测试BPN 15606将降低C99和Aβ42水平的治疗假设 以防止和/或减轻神经变性。测试的机械假设是，BPN 15606将 使内体结构和功能、神经营养因子信号传导和运输正常化，并改善 认知.广泛的药理学/毒理学研究证明BPN 15606适用于我们的研究。具体目标：1。详细说明 AD-DS和AD/脑淀粉样变性小鼠模型中神经退行性变的发生。Dp 16模型的研究 将提交AD-DS和AD的Line 41模型进行形态学的无偏倚体视学研究， 生物化学，以定量定义神经元和突触变性的开始（Dp 16：LCN，BFCN; Line 41：BFCN，CA 3），出现p-Tau和淀粉样蛋白斑块。2.检查BPN 15606治疗的效果 在AD-DS模型中神经变性发作之前和之后。Dp 16和2N小鼠将用以下药物治疗： 有效安全剂量的BPN 15606。在量化的GO/NOGO标准的指导下， 将评估加工导致退化、内体和认知表型的减轻。3.到 在AD/脑神经变性发作之前和之后检查BPN 15606治疗的效果 淀粉样变性模型。相同的方法将指导在Line 41小鼠中进行的BPN 15606研究。BPN 15606介导的 变性的减少将支持治疗假设;内体和认知功能的正常化 表型将支持机械假说。这些研究旨在为以下试验提供信息和指导： AD-DS中的BPN 15606。