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

摘要

Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) 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 Abeta accumulation. RARalpha 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 Abeta production. We also show that RARalpha agonists are neuroprotective, as they prevent Abeta-induced neuronal cell death in cortical cultures. If RARalpha agonists are given to the Tg2576 mouse, the normal Abeta production in their brains is suppressed. In contrast, neither RARbeta nor gamma-agonists affect Abeta production or Abeta-mediated neuronal cell death. Therefore, RARalpha agonists have therapeutic potential for the treatment of AD.