Amyloid beta inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor beta agonist

作者：Goncalves Maria B; Clarke Earl; Hobbs Carl; Malmqvist Tony; Deacon Robert; Jack Julian; Corcoran Jonathan P T^*

来源：European Journal of Neuroscience, 2013, 37(7): 1182-1192.

DOI：10.1111/ejn.12142

• Alzheimer's disease
• amyloid clearance
• insulin-degrading enzyme
• neprilysin
• retinoic acid

The retinoic acid receptor (RAR) system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RAR signalling is down-regulated by amyloid beta (A), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RAR-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RAR agonist. RAR signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes A clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RAR signalling prevents tau phosphorylation. Therefore, stimulation of the RAR signalling pathway using a synthetic agonist, by both clearing A and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

• 出版日期2013-4