Monomeric A beta 1-42 and RAGE: key players in neuronal differentiation

The aggregation of amyloid- beta (A beta ) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of A beta , indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric A beta 1-42 in ATRA-induced neuronal differentiation has been investigated. Four-day ATRA treatment increases beta -secretase 1 (BACE1) level, A beta 1-42 production, and receptor for advanced glycation end-products (RAGE) expression. RAGE is a well-recognized receptor for A beta , and the block of both RAGE and A beta 1-42 with specific antibodies strongly impairs neurite formation in ATRA-treated cells. The involvement of A beta 1-42 and RAGE in ATRA-induced morphologic changes has been confirmed treating undifferentiated cells with different molecular assemblies of peptide: 1 mu M monomeric, but not oligomeric, A beta 1-42 increases RAGE expression and favors neurite elongation. The block of RAGE completely prevents this effect. Furthermore, our data underline the involvement of the RAGE-dependent adhesion molecule amphoterin-induced gene and open reading frame-1 as downstream effector of both ATRA and A beta 1-42. In conclusion, our findings identify a novel physiological role for monomeric A beta 1-42 and RAGE in neuronal differentiation.