Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β

Alzheimer's disease (AD) is characterized by amyloid-beta (A beta) deposition in the brain, neuronal cell loss and cognitive decline. We show here that retinoic acid receptor (RAR)alpha signalling in vitro can prevent both intracellular and extracellular A beta accumulation. RAR alpha signalling increases the expression of a disintegrin and metalloprotease 10, an alpha-secretase that processes the amyloid precursor protein into the non-amyloidic pathway, thus reducing A beta production. We also show that RAR alpha agonists are neuroprotective, as they prevent A beta-induced neuronal cell death in cortical cultures. If RAR alpha agonists are given to the Tg2576 mouse, the normal A beta production in their brains is suppressed. In contrast, neither RAR beta nor gamma-agonists affect A beta production or A beta-mediated neuronal cell death. Therefore, RAR alpha agonists have therapeutic potential for the treatment of AD.