Title:Every Cloud Has a Silver Lining: Proneurogenic Effects of Aβ Oligomers and HMGB-1 via Activation of the RAGE-NF-κB Axis
Volume: 16
Issue: 10
Author(s): Valeria Bortolotto and Mariagrazia Grilli*
Affiliation:
- Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale "Amedeo Avogadro", Via Bovio 6, 28100 Novara,Italy
Keywords:
Alzheimer's disease, NF-κB, RAGE, HMGB-1, Aβ, oligomers, neurogenesis, neuroinflammation.
Abstract: Background & Objective: Since its initial discovery, current understanding on the functional
role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology
has impressively grown, especially in consideration of its large ligand repertoire (AGEs,
HMGB-1, β amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several
chronic human disorders. Downstream RAGE engagement by its ligands, NF-κB signaling activation
has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation
that in Alzheimer's Disease (AD) brain expression of RAGE and its ligands is upregulated and that
RAGE/NF-κB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation
and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD
pathophysiology. Herein we review the vast array of information supporting a detrimental role of
RAGE/NF-κB axis activation in AD brain and discuss those data in the context of recent findings obtained
in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may
rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly,
the proneurogenic effect resulting from RAGE/NF-κB axis activation could be induced by
molecules which are commonly considered as mediators of toxicity, like Aβ oligomers and HMGB-1.
Conclusion: Altogether, despite a large set of data suggesting that RAGE may represent an interesting
target for the pharmacological treatment of AD, the complex functional roles of the receptor would require
the use of molecules able to counteract RAGE negative effects without altering the positive ones
such as the promotion of adult neurogenesis.
