Promoting adult hippocampal neurogenesis in Alzheimer's Disease Models

促进阿尔茨海默病模型中的成人海马神经发生

• 批准号: 10288508
• 负责人: JUSTIN R. FALLON
• 金额: $ 45.06万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288508
• 关键词: 3xTg-AD mouse; Adult; Affinity; Aging; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Animals; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Behavior; Binding; Birth; Brain; Characteristics; Cognition; Defect; Disease; Drug Kinetics; Engineering; Environment; Exhibits; Hippocampus (Brain); Human; Impaired cognition; Impairment; Inflammatory; Knock-in Mouse; Learning; Length; Life; Longevity; Memory; Modeling; Mus; Neurons; Pathologic; Pathway interactions; Pharmaceutical Preparations; Reporting; Safety; Senile Plaques; Shapes; Signal Transduction; Spinal Muscular Atrophy; Testing; Therapeutic; Work; conditional mutant; efficacy testing; exon skipping; experimental study; improved; mouse model; nerve stem cell; neurogenesis; newborn neuron; receptor; success

Project Summary Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory and reduced AHN is an early hallmark of Alzheimer’s Disease (AD). Thus, restoring AHN has emerged as an attractive target for AD therapy. The accumulation of negative signals that degrade the neurogenic niche contributes to the reduction in newborn neurons in AD and aging. BMPs are components of the niche that negatively regulate neurogenesis and their levels are increased in AD in humans and in mouse FAD models. We recently reported that full length MuSK harboring its Ig3 domain, which is necessary for high affinity BMP binding, is a BMP co-receptor that augments and shapes BMP signaling. In preliminary studies we established that MuSK is endogenously expressed in neural stem cells (NSCs). We generated knock-in mice engineered to constitutively express an alternatively spliced form of MuSK lacking the Ig3 domain (‘ΔIg3- MuSK’). The animals are viable, fertile and have a normal life span. NSCs isolated from ΔIg3- MuSK mice show impaired BMP responsiveness. Remarkably, the ΔIg3-MuSK mice exhibit over a two-fold increase in AHN and improved hippocampal-dependent learning. These results suggest that reducing MuSK-BMP activity by modulating MuSK alternative splicing is a potential target for promoting AHN in AD. Importantly, such alternative splicing is expected to be amenable to manipulation by exon-skipping antisense oligonucleotides. The recent success of the ASO Spinraza for Spinal Muscular Atrophy has demonstrated that this class of drugs can be highly effective in the human CNS, with a favorable pharmacokinetic and safety profile. In the proposed experiments we will use mouse FAD models to test whether inhibition of the MuSK- BMP pathway can promote AHN in the plaque-rich and inflammatory ‘AD environment’. To more closely model the pathological and therapeutic landscape in humans, we will also use conditional mutants to test whether manipulating the MuSK-BMP pathway after amyloid plaque formation can promote AHN and improve cognition. If successful, this work will form an important part of the rationale and impetus for a pursuing a MuSK-directed ASO therapy for AD.

项目摘要 成年海马神经发生（AHN）对于正常的学习和记忆至关重要， AHN是阿尔茨海默病（AD）的早期标志。因此，恢复AHN已成为一种 有吸引力的AD治疗靶点。负面信号的积累降低了 神经原性生态位有助于AD和衰老中新生神经元的减少。bmp是 负调节神经发生的小生境成分，它们的水平增加， 在人类和小鼠FAD模型中的AD。我们最近报道说，全长MuSK窝藏 其Ig 3结构域是高亲和力BMP结合所必需，是BMP共受体， 增强和塑造BMP信号传导。在初步研究中，我们确定MuSK是 在神经干细胞（NSC）中内源性表达。我们制造了基因敲入小鼠 以组成型表达缺少Ig 3结构域的MuSK的可变剪接形式（“Δ Ig 3-”）， MuSK“）。动物是可行的，肥沃的，并有一个正常的寿命。从Δ Ig 3- MuSK小鼠显示受损的BMP反应性。值得注意的是，Δ Ig 3-MuSK小鼠表现出超过 AHN增加了两倍，并改善了依赖于大脑的学习能力。这些结果 提示通过调节MuSK选择性剪接来降低MuSK-BMP活性是一种潜在的 在AD中促进AHN的靶点。重要的是，这种选择性剪接预计将是 易于通过外显子跳跃反义寡核苷酸进行操作。最近的成功 用于脊髓性肌萎缩症的阿索已经证明这类药物可以 在人CNS中高度有效，具有有利的药代动力学和安全性特征。在 建议的实验，我们将使用小鼠FAD模型来测试是否抑制MuSK- BMP通路可以促进AHN在斑块丰富和炎性的“AD环境”中。更 密切模拟人类的病理和治疗景观，我们还将使用 条件突变体，以测试在淀粉样斑块后是否操纵MuSK-BMP通路 形成可以促进AHN，改善认知。如果成功，这项工作将形成一个 这是寻求MuSK导向的阿索治疗AD的基本原理和动力的重要部分。