ECM regulation and neuronal plasticity in mice harboring a common risk allele for Alzheimer's

携带阿尔茨海默病常见风险等位基因的小鼠的 ECM 调节和神经元可塑性

• 批准号: 10615111
• 负责人: Katherine E Conant
• 金额: $ 39万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615111
• 关键词: Abeta clearance; Acceleration; Address; Adult; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Antidepressive Agents; Apolipoprotein E; Area; Astrocytes; Attenuated; Behavioral; Binding; Brain; CCR5 gene; CSPG3 gene; Central Nervous System; Cognition; Cognitive; Data; Dendrites; Deposition; Disintegrins; Dose; Elderly; Enzyme Tests; Equilibrium; Event; Extracellular Matrix; FDA approved; Family member; Fluorescence; Future; Gelatinase B; Glutamates; Hippocampus; Human; Impaired cognition; Impairment; Individual; Interneurons; Learning; Lectin; Link; Long-Term Effects; Long-Term Potentiation; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Memory impairment; Metalloproteases; Mus; Nerve Degeneration; Neuronal Plasticity; Neurons; Parvalbumins; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Play; Population Dynamics; Proteolysis; Publishing; Pyramidal Cells; RANTES; Regulation; Reversal Learning; Risk; Rodent; Short-Term Memory; Slow-Wave Sleep; Stains; Testing; Therapeutic; Time; Tissue Inhibitor of Metalloproteinase-1; Western Blotting; aged; aggrecan; antagonist; apolipoprotein E-4; brevican; chemokine; cognitive reserve; cohort; collagenase 3; critical period; experience; experimental study; flexibility; gamma-Aminobutyric Acid; memory consolidation; neuronal cell body; neurotransmission; post stroke; preclinical study; receptor; risk variant; transmission process; venlafaxine

Abstract The three human alleles of Apolipoprotein E (APOE) differentially impact individual risk for Alzheimer’s disease (AD), with the APOE4 allele significantly increasing risk in a dose dependent manner. The mechanisms by which APOE4 elevates AD risk are not fully understood. As compared to other alleles, APOE4 may reduce clearance of amyloid-β (Aβ) from the central nervous system. Moreover, in mice with targeted replacement (TR) of APOE or APOE3, APOE4 TR mice show a relative reduction in dendritic complexity and impaired learning. This is significant in that these mice do not deposit Aβ, suggesting that APOE4 might independently reduce cognitive reserve and thus enhance vulnerability to AD and cognitive decline. Consistent with this is a more recent study of sharp wave ripple (SWR) abundance, in which SWR abundance was reduced in APOE4 TR mice. SWRs are events in which assemblies of hippocampal neurons, sequentially activated as a function of time and place during a learning experience, are sequentially replayed in an accelerated fashion during quiet restfulness and slow wave sleep. Replay is critical to memory consolidation and to transfer of hippocampal encoded experience to cortical areas for long term storage. Accumulating evidence suggests that deficits in neuronal plasticity, including reduced pyramidal cell arborization and SWR abundance, may be due in part to alterations in brain extracellular matrix (ECM) including perineuronal nets (PNNs). PNNs are a specialized form of ECM predominantly localized to the soma and proximal dendrites of gamma aminobutyric acid (GABA) releasing parvalbumin (PV) expressing inhibitory interneurons, and they facilitate GABAergic inhibitory transmission to constrain excitatory neuroplasticity. Indeed, maturation of PNNs coincides with the closure of critical periods of enhanced physiological plasticity. Conversely, drugs that attenuate PNN abundance can increase long term potentiation (LTP) of hippocampal neurotransmission, plasticity of glutamatergic neurotransmission, cognitive flexibility and SWR abundance in adult rodents. In the present proposal, we outline plans to test the hypothesis that APOE4 is linked to a dysregulation of the balance between PNN deposition and proteolysis, and that it is this imbalance that leads to deficits including reduced SWR abundance. This hypothesis is based on published and preliminary data discussed in the background. In this proposal, we also outline plans to test the hypothesis that two FDA approved compounds, venlafaxine and maraviroc, will normalize ECM levels and physiological changes observed in APOE4 TR mice including reduced SWR abundance. Venlafaxine is an antidepressant medication with the potential to increase matrix metalloproteinase-9 (MMP-9) levels and attenuate the PNN, while maraviroc is instead an antagonist for CCR5, a hypothetical regulator of the ECM. The CCL5 receptor, CCR5, restricts LTP and post-stroke neuroplasticity, while both LTP and plasticity are instead increased in CCL5-receptor antagonist treated mice.

摘要 人类载脂蛋白E(APOE)的三个等位基因对阿尔茨海默病的个体风险有不同的影响 疾病(AD)，APOE4等位基因以剂量依赖的方式显著增加风险。其作用机制 APOE4是如何增加AD风险的，目前还不完全清楚。与其他等位基因相比，APOE4可能减少 淀粉样蛋白-β(A-β)从中枢神经系统的清除。此外，在靶向替代(Tr)的小鼠中 在APOE或APOE3中，APOE4tr小鼠表现出树突复杂性的相对降低和学习障碍。 这一点很重要，因为这些小鼠不会沉积Aβ，这表明载脂蛋白4可能独立地减少 认知储备，从而增强对阿尔茨海默病和认知衰退的易感性。与此一致的是一个更多的 尖波纹波丰度的最新研究，其中尖波纹波丰度在APOE4树中降低 老鼠。SWR是一种事件，在这种事件中，海马神经元的组装顺序地被激活为 学习体验中的时间和地点，在安静时以加速的方式顺序重播 宁静和慢波睡眠。重放对记忆巩固和海马区转移至关重要 编码体验到皮质区域，以便长期存储。越来越多的证据表明， 神经元的可塑性，包括锥体细胞分支减少和SWR丰度，可能部分归因于 脑细胞外基质(ECM)包括神经周围神经网络(PNNS)的变化。PNN是一种特殊形式 细胞外基质主要定位于γ-氨基丁酸(GABA)胞体和近端树突 释放表达抑制性中间神经元的小白蛋白(PV)，促进GABA能抑制 传递以抑制兴奋性神经可塑性。事实上，PNNS的成熟恰逢 增强生理可塑性的关键时期。相反，减少PNN丰度的药物可以 增强海马神经传递长时程增强、谷氨酸能可塑性 成年啮齿动物的神经传递、认知灵活性和SWR丰度。在本提案中，我们概述了 计划测试这一假设，即APOE4与PNN沉积和PNN之间的平衡失调有关 蛋白质分解，正是这种不平衡导致了包括SWR丰度降低在内的缺陷。这一假设 是基于已公布的和在背景中讨论的初步数据。在这项提案中，我们还概述了计划 为了验证FDA批准的两种化合物文拉法辛和马拉韦罗将使ECM水平正常化的假设 在APOE4tr小鼠中观察到的生理变化包括SWR丰度降低。文拉法辛是一种 抗抑郁药物可能增加基质金属蛋白酶-9(MMP-9)水平和 减弱PNN，而马拉韦罗则是CCR5的拮抗剂，CCR5是ECM的假想调节器。这个 CCL5受体CCR5限制LTP和卒中后神经可塑性，而LTP和可塑性则相反 CCL5受体拮抗剂处理的小鼠增加。