载脂蛋白E基因型特异性与血管周围细胞相互作用及调节Aβ的病理机制研究

Alzheimer’s disease (AD) is characterized by cerebrovascular and neuronal dysfunctions leading to a progressive decline in cognitive functions.The accumulation of amyloid-β (Aβ) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of AD. The binding of Aβ peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. .Brain perivascular macrophages （PC）are CD163 and CD206 positive immune cells located in outer aspects of blood vessels within the brain. PC are antigen-presenting phagocytotic cells, and have been shown to respond to CNS inflammation. Blood-derived macrophages from AD patients were shown to be less effective at phagocytosing Aβ compared with cells derived from non-demented control patients. It has also been shown that Aβ induces migration of monocytes across the human BBB. .Perivascular drainage of the extracellular fluid of the brain is one of the clearance mechanisms for proteins in the brain. Proteins that are produced in the brain are cleared into the perivascular space..Clodronate-mediated depletion of PC in vivo significantly increased CAA in TgCRND8 AD transgenic mice, whereas chitin stimulated PC turnover and promoted Aβ clearance.We have reported that blocking the apoE/Aβ Interaction Reduces Fibrillar Vascular Amyloid Deposition, Aβ toxicity and Cerebral Microhemorrhages in TgSwDI Mice.The APOE E4 allele is the major risk factor for sporadic AD， apoE is found in vessel wall lesions and its E4 allele is associated with the severity of the disease.For Aβ as well as for apoE, it could be shown that the proteins produced by astrocytes (apoE) or neurons (Aβ) occur in the perivascular space of transgenic mice expressing a human-specific form of apoE in astrocytes.Since apoE and Aβ are cleared through the perivascular space and possibly through the vessel walls along the basement membranes, it should be expected that perivascular drainage receives relevance for AD in which one or both of these proteins are involved. .We propose that the pathogenic apoE4 variant is less functional than the E3 at promoting apoptotic cell clearance. Over a lifetime, this marginal deficiency leads to an accumulation of uncleared apoptotic cell remnants in the brain, as well as the establishment of a subtle pro-inflammatory phenotype. Eventually, these two can combine to damage the the brain, to such an extent that functional deficits begin to appear. We are currently investigating the validity of this hypothesis, initially we examined Aβ phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls with differente ApoE phenotypes, and eventually also in transgenic mice lines expressing either human E3 or E4 on a murine apoE-deficient background, we will study the interaction of apoe, PC and amyloid clearance,it could possibly have major implications for AD.

AD主要是由于β淀粉样蛋白（Aβ）在脑中积聚形成Aβ斑块，从而导致神经元细胞死亡，导致破坏性记忆丧失及其他精神异常，研究结果显示, 脑内的Aβ的产生与清除的不平衡导致了老年斑的沉积。 本课题研究载脂蛋白E亚型特异性作用于Aβ及神经细胞，在充分的前期工作基础上拟对载脂蛋白E亚型与脑血管周围吞噬细胞的特异性相互作用，改变动物行为和调节脑内Aβ的机制进行进一步研究。首先采用APP/APOE不同亚型小鼠为研究对象，通过激活和清除不同各组载脂蛋白E亚型（基因敲除,E3,E4）鼠的脑血管周围细胞，观察小鼠的行为改变，脑Aβ水平变化及老年斑的沉积情况进行研究。然后通过PET-PIB诊断的携带载脂蛋白E3和E4的AD患者血液的单核细胞分化成吞噬细胞的能力及对Aβ蛋白的吞噬水平进行研究，从而揭示不同载脂蛋白E亚型与脑血管周围细胞的特异性相互作用和对Aβ清除作用，研究结果可为AD治疗提供依据。

AD主要是由于β淀粉样蛋白（Aβ）在脑中积聚形成Aβ斑块，从而导致神经元细胞死亡，导致破坏性记忆丧失及其他精神异常，研究结果显示, 脑内的Aβ的产生与清除的不平衡导致了老年斑的沉积。本课题研究发现APOE对AD患者老年斑沉积的影响与单核细胞的吞噬功能有关。APP+ApoE 鼠的 PC 再生率（Turnover）受 ApoE 亚型的影响；PC随着年龄的增加而减少; 不同亚型的 ApoE鼠，PC的密度也有明显不同。AD 患者的 PC 的吞噬 Aβ 功能与正常健康者比较明显减退。APOEε4是FTLD患者的遗传危险因素，对APOE基因型与卒中之间的关系研究表明ApoE等位基因类型与卒中亚型之间无显着关联。对FTLD亚型的临床表现与影像学检查（MRI,PIB-PET,FDG-PET）分析表明 87.7％的FTLD病例发现脑叶萎缩。日常生活活动量表，MMSE和MOCA认知评估得分与总体萎缩程度显着相关。对痴呆照料者的几项研究表明抑郁症，焦虑症和睡眠问题是阿尔茨海默氏病患者的家庭护理人员面临的主要挑战。与阿尔茨海默氏病患者相比，路易体痴呆患者和额颞叶变性痴呆表现出明显更多的神经精神症状。在额颞叶变性和路易氏体痴呆的照顾者中，神经精神症状，PHQ-9评分和GAD-7评分可预测患者的负担。