Modulation of neurodegeneration and neuroinflamation by the liver X receptor (LXR) in Alzheimer`s disease

来自第一个资助期的体外证据表明星形胶质细胞LXRa和ApoE的表达对指导小胶质细胞摄取asb至关重要。这一发现将在体内得到验证。因此，我们将在体内用甲氧基- x04标记亚ß，然后分离小胶质细胞，用FACS定量测定甲氧基- x04标记的亚ß的吞噬情况。此外，我们还将利用双光子生命显微镜研究阿斯吞噬作用。由于LXR介导的ApoE脂化也可能影响asas的聚集，因此LXR刺激下ApoE脂化的变化会影响asas与ApoE的结合从而影响asas的聚集，我们将在体外研究并在体内证实。我们打算进一步研究ApoE3和ApoE4对LXR刺激改变APP/PSI小鼠病理和行为能力的影响。我们预计，ApoE4将削弱在LXR刺激下观察到的积极作用，从而进一步阐明ApoE4作为AD风险因素的作用。为了确定星形胶质细胞表达的LXRa在吞噬星形胶质细胞中的作用，我们将星形胶质细胞特异性条件LXRa敲除小鼠与APP/PS1小鼠杂交。在所有相关小鼠品系中，将通过qPCR对炎症介质和asb清除蛋白进行定量，以获得asb吞噬过程中促炎或抗炎作用的证据。

In vitro evidence from the first funding period suggests that astroglial LXRa and ApoE expression are critical to guide microglial Aß uptake. This finding will now be validated in vivo. Therefore, Aß will be labelled in vivo by methoxy-X04 and subsequently microglia isolated to quantify methoxy- X04-labelled Aß phagocytois by FACS. In addition, Aß phagocytosis will be studied using 2- photon life microscopy. Since LXR mediated lipidation of ApoE may also affect aggregation of Aß, changes of ApoE lipidation upon LXR stimulation affecting the binding of Aß to ApoE and thereby Aß aggregation will be studied in vitro and confirmed in vivo. We further intend to study the effect of ApoE3 and ApoE4 on the ability of LXR stimulation to alter pathology and behaviour in APP/PSI mice. We expect that ApoE4 will impair the positive effects observed in response to LXR stimulation and thereby further elucidating the role of ApoE4 as an AD risk factor. To define a role of astrocyte-expressed LXRa for Aß phagocytosis, astrocyte specific conditional LXRa knockout mice will cross-bred with APP/PS1 mice. In all relevant mouse strains, inflammatory mediators and Aß scavenging proteins will be quantified by qPCR to obtain evidence for a pro- or anti-inflammatory contribution in the phagocytosis of Aß.