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

• Published in: The European journal of neuroscience Vol. 37; no. 7; pp. 1182 - 1192
• Main Authors: Goncalves, Maria B., Clarke, Earl, Hobbs, Carl, Malmqvist, Tony, Deacon, Robert, Jack, Julian, Corcoran, Jonathan P. T.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.04.2013; Blackwell
• Subjects: Adult and adolescent clinical studies; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; amyloid β clearance; amyloid β clearance, insulin‐degrading enzyme; Animals; Benzoates - pharmacology; Biological and medical sciences; Cognition - drug effects; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disorders of the Nervous System; Down-Regulation; insulin-degrading enzyme; Insulysin - metabolism; Medical sciences; Mice; Microglia - metabolism; neprilysin; Neprilysin - metabolism; Neurology; Neurons - metabolism; Organic mental disorders. Neuropsychology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; retinoic acid; Retinoid X Receptor alpha - agonists; Retinoid X Receptor alpha - metabolism; Signal Transduction; Tetrahydronaphthalenes - pharmacology; Tretinoin - metabolism; insulin-degrading enzyme; Nervous system diseases; Agonist; Enzyme; Alzheimer disease; Retinoid; Insulysin; Metalloendopeptidases; Clearance; RARα retinoic acid receptor; Cerebral disorder; Peptidases; β Amyloid protein; Central nervous system disease; amyloid β clearance; Hydrolases; Degenerative disease; Neprilysin; Retinoic acid; Alzheimer's disease
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12142

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 RARα 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 RARα‐activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα 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, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα 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. 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 RARα signalling is down regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA).