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 载脂蛋白E（APOE）的三种人类等位基因对阿尔茨海默病个体风险的影响差异 AD患者的APOE 4等位基因以剂量依赖性方式显著增加风险。的机制 APOE 4升高AD风险的机制尚未完全了解。与其他等位基因相比，APOE 4可以减少 从中枢神经系统清除淀粉样蛋白-β（Aβ）。此外，在靶向替代（TR）小鼠中， APOE或APOE 3、APOE 4 TR小鼠的树突复杂性相对降低，学习能力受损。 这是有意义的，因为这些小鼠不存款Aβ，这表明APOE 4可能独立地减少A β的表达。 认知储备，从而增强对AD和认知下降的脆弱性。与此相一致的是， 最近对尖波涟漪（SWR）丰度的研究，其中在APOE 4 TR中SWR丰度降低 小鼠SWRs是海马神经元的组装体，作为海马神经元的功能被顺序激活的事件。 时间和地点，在学习经验，是按顺序重放在一个加速的方式，在安静的 宁静和慢波睡眠。重放对记忆巩固和海马神经元的迁移起着重要作用 编码的经验到皮层区域进行长期存储。越来越多的证据表明， 神经元的可塑性，包括减少锥体细胞树枝状和SWR丰度，可能部分是由于 脑细胞外基质（ECM）包括神经元周网（PNN）的改变。PNN是一种特殊形式 ECM主要定位于γ-氨基丁酸（GABA）的索马体和近端树突 释放表达抑制性中间神经元的小清蛋白（PV），并且它们促进GABA能抑制性中间神经元， 传递以限制兴奋性神经可塑性。事实上，PNN的成熟与 生理可塑性增强的关键时期。相反，减少PNN丰度的药物可以 增加海马神经传递长时程增强（LTP）、海马神经元可塑性 神经传递，认知灵活性和SWR丰富的成年啮齿动物。在本提案中，我们概述了 计划测试APOE 4与PNN沉积和PNN沉积之间平衡失调有关的假设。 蛋白水解，并且正是这种不平衡导致包括减少的SWR丰度的缺陷。这一假设 基于背景中讨论的公开和初步数据。在这份提案中，我们还概述了 为了验证两种FDA批准的化合物文拉法辛和马拉韦罗将使ECM水平正常化的假设， 以及在APOE 4 TR小鼠中观察到的生理变化，包括减少的SWR丰度。文拉法辛是一种 具有增加基质金属蛋白酶-9（MMP-9）水平潜力的抗抑郁药物， 减弱PNN，而马拉韦罗是CCR 5的拮抗剂，CCR 5是ECM的假设调节剂。的 CCL 5受体，CCR 5，限制LTP和中风后神经可塑性，而LTP和可塑性， 在CCL 5受体拮抗剂处理的小鼠中增加。