Liver X receptors: Emerging therapeutic targets for Alzheimer's disease

Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathological accumulation of ß-amyloid peptides (Aß) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiological and biochemical data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Aß, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRß) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathology through multiple pathways. Reports indicate that genetic loss of either lxra or lxrß in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Aß production with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biology of LXRs, with an emphasis on their probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.

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