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Amyloid β inhibits retinoic acid synthesis exacerbating A lzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist
Author(s) -
Goncalves Maria B.,
Clarke Earl,
Hobbs Carl,
Malmqvist Tony,
Deacon Robert,
Jack Julian,
Corcoran Jonathan P. T.
Publication year - 2013
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12142
Subject(s) - retinoic acid , agonist , retinoic acid receptor , microbiology and biotechnology , chemistry , receptor , pharmacology , neuroscience , biology , biochemistry , gene
The retinoic acid receptor ( RAR ) α 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 α signalling is down‐regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid ( RA ). This results in the counteraction of a variety of RAR α‐activated pathways that are key in the aetiopathology of Alzheimer's disease ( AD ) but which can be reversed by an RAR α agonist. RAR α signalling improves cognition in the Tg2576 mice, it has an anti‐inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RAR α signalling prevents tau phosphorylation. Therefore, stimulation of the RAR α signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD .