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

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