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.

我们的目标是通过以下方法预防患有DS(21三体)的成人阿尔茨海默病(AD)，即DS中的AD(AD-DS) 加强淀粉样前体蛋白(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：1)增加APP基因剂量是必要的 AD-DS，这一发现在DS的小鼠模型中重复。通过归一化DS模型中的APP剂量，我们消除了：a) 蓝斑(LCNs)和基底前脑复合体(BFCNs)神经元的增龄性变性 Tau的磷酸化，以及c)早期内小体的增大；2)C99和Aβ42通过增加而起作用 激活Rab5以诱导内小体改变，从而减少神经营养信号的运输 BFCN萎缩。证据表明，增加的C99和Aβ42通过缺乏 神经营养信号的内体运输和激励治疗以减少C99和Aβ42。因为两者都 是γ分泌酶的底物，增加γ分泌酶活性应该会降低水平，防止或减轻 内体和退行性表型。γ分泌酶调节剂BPN15606增加γ分泌酶 活动。在体外，BPN15606有效地减少了C99和Aβ42，降低了Rab5的激活，并恢复了内体 神经营养因子的大小和贩运。在体内，它逆转了内体增大，增加了LCN数量， 逆转Tau的过度磷酸化和增强认知。AD-DS和AD/脑损伤小鼠模型的建立 我们将检验BPN15606将降低C99和Aβ42水平的治疗假说 预防和/或减轻神经退行性变。经过检验的机械假说是BPN15606将 使内体结构和功能正常化，神经营养因子信号和运输正常化，并改善 认知力。广泛的PARM/TOX研究使BPN15606有资格进行我们的研究。具体目标：1.详细说明时间 阿尔茨海默病和阿尔茨海默病/脑淀粉样变性小鼠模型中神经退行性变的发生。Dp16模型的研究 AD-DS和41行AD模型将提交无偏见的形态和体视学研究 生物化学，定量定义神经元和突触变性的开始(Dp16：LCNs，BFCNs；Line 41：BFCNs，CA3)，出现p-Tau和淀粉样斑块。2.观察BPN15606的治疗效果 在AD-DS模型中，神经退行性变发生前后。Dp16和2N小鼠将接受一种 有效、安全剂量的BPN15606。在量化GO/NOGO标准的指导下，增强的APP的程度 将对减少退变、内体和认知表型的处理结果进行评估。3.至 检测BPN15606在AD/脑内神经变性发病前后的作用 淀粉样变性模型。同样的方法将指导BPN15606在Line 41小鼠上的研究。BPN15606-中介 退变的减少将支持治疗假说；内体和认知的正常化 表型将支持机械论假说。这些研究旨在通知和指导临床试验 AD-DS中的BPN15606。