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.

抽象的 载脂蛋白E（APOE）的三个人类等位基因对阿尔茨海默氏症的个人风险有所不同 疾病（AD），APOE4等位基因以剂量依赖的方式显着增加了风险。机制 APOE4提高AD风险的情况尚不完全了解。与其他等位基因相比，APOE4可能会减少 从中枢神经系统清除淀粉样蛋白-β（Aβ）。此外，在靶向替换（TR）的小鼠中 APOE或APOE3的APOE4 TR小鼠显示了树突复杂性和学习受损的相对降低。 这很重要，因为这些小鼠没有沉积Aβ，这表明APOE4可能会独立减少 认知储备，从而增强了AD和认知下降的脆弱性。与此一致的是 最近对尖锐波纹波（SWR）抽象的研究，其中SWR抽象降低了APOE4 TR 老鼠。 SWR是事件，其中海马神经元的组装，依次激活的函数 在学习体验期间的时间和地点，在安静期间以加速方式依次重播 宁静和慢波睡眠。重播对记忆合并和海马转移至关重要 为长期存储的皮质区域编码经验。累积证据表明在 神经元可塑性，包括降低的锥体细胞伪造和SWR抽象，可能部分归因于 脑细胞外基质（ECM）的改变，包括周神经元网（PNNS）。 PNN是一种专业形式 ECM主要定位于伽马氨基丁酸（GABA）的SOMA和近端树突 释放表达抑制性神经元的白蛋白（PV），它们促进GABA能抑制作用 传播以限制兴奋性神经质量。确实，PNN的成熟与关闭相吻合 增强生理可塑性的关键时期。相反，减弱PNN丰度的药物可以 增加海马神经传递的长期增强（LTP），谷氨酸能的可塑性 成年啮齿动物中的神经传递，认知灵活性和SWR抽象。在本提案中，我们概述了 计划测试APOE4与PNN沉积与PNN沉积之间平衡失调有关的假设 蛋白水解，正是这种不平衡导致定义了包括SWR丰度减少。 基于背景中讨论的已发布和初步数据。在此提案中，我们还概述了计划 为了检验两个FDA批准的化合物Venlafaxine和Mariviroc的假设，将使ECM水平正常化 以及在APOE4 TR小鼠中观察到的身体变化，包括降低SWR抽象。 Venlafaxine是一个 抗抑郁药具有增加基质金属蛋白酶-9（MMP-9）水平的潜力 减轻PNN，而Maraviroc则是CCR5的拮抗剂，CCR5是ECM的假设调节剂。这 CCL5受体CCR5限制了LTP和中风后神经可塑性，而LTP和可塑性都是 CCL5受体拮抗剂治疗的小鼠的增加。