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

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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.