Modulation of neurodegeneration and neuroinflammation by the Liver X receptor (LXR) in Alzheimer’s disease (AD)
Liver X receptor (LXR) in Alzheimer's disease (AD)
AD is typified by the accumulation of β-amyloid (Aβ) deposits accompanied with neuronal degeneration and a microglial inflammatory response. This application explores the role of the liver X receptors (LXRs) in AD-related neuroinflammation and tests the hypothesis that LXR activation exerts beneficial effects on AD pathology. The principal function of the two members of the LXR family, LXRα and LXRβ, is to regulate cholesterol homoeostasis. Importantly, LXRs positively regulate ApoE, the principal apolipoprotein in the brain and influences Aβ deposition and clearance. Another target is the ABC transporter, ABCA1, which mediates directed transport of ApoE. Moreover, LXR agonists transcriptionally repress inflammatory genes in macrophages and microglia. Importantly, ABCA1 expression is dramatically induced in neurons, astrocytes and microglia upon LXR activation and LXR agonists reduce Aβ levels in APP23 mice. However, neuronal Aβ production is not likely to be the dominant effect of LXRs in AD. Recent studies have reported that inactivation of the LXR target gene, ABCA1, lowered brain ApoE levels and increased Aβ plaque burden. Therefore the principal effect of LXR and ABCA1 in the brain is to affect the propensity of Aβ to be deposited and/or to facilitate its clearance. Own preliminary data demonstrate that prolonged treatment of APP mice with an LXR agonist reduces Aβ and microglia activation significantly. We hypothesize that LXR-mediated modification of microglial functions alters AD pathology and in particular Aβ deposition and clearance. This hypothesis will be tested by the following studies. First, APP/PS1 mice will be brought on a LXRα-/-, LXRβ-/- or a double knockout background. The respective mouse lines will be characterized in terms of behaviour, neuropathology (Aβ deposition, neuroinflammation, synaptic loss, axonal damage) and changes in APP processing. Second, similar studies will be carried out in APP/PS1 mice acutely or chronically treated with LXR agonists. Third, the mechanism of fibrillar Aβ uptake by microglial cells in response to LXR agonists or LXRα/β deficiency, with emphasis on its dependence on ApoE/ABCA1, will be elucidated in cultures of microglial cells or co-cultures of microglial and astroglial cells.