title: High-mobility group box-1 protein and β-amyloid oligomers promote neuronal differentiation of adult hippocampal neural progenitors via receptor for advanced glycation end products/nuclear factor-κB axis: relevance for Alzheimer's disease.
abstract: Dysregulated hippocampal neurogenesis has been associated with neurodegenerative disorders, including Alzheimer's disease (AD), in which it may potentially represent an auto-reparatory mechanism that could counteract neuronal loss and cognitive impairment. We evaluated hippocampal neurogenesis in TgCRND8 mice and reported that, at 32 weeks of age, corresponding to an advanced AD-like neuropathology stage, increased numbers of proliferating cells, doublecortin-expressing progenitors/neuroblasts, and early postmitotic calretinin-expressing neurons were present compared with wild-type (WT) littermates. When hippocampal neural progenitor cells (NPCs) were isolated from TgCRND8 mice, we demonstrated that (1) their neurogenic potential was higher compared with WT NPCs; (2) medium conditioned by TgCRND8 NPC promoted neuronal differentiation of WT NPCs; and (3) the proneurogenic effect of TgCRND8-conditioned medium was counteracted by blockade of the receptor for advanced glycation end products (RAGE)/nuclear factor-κB (NF-κB) axis. Furthermore, we showed that β-amyloid 1-42 (Aβ(1-42)) oligomers, but not monomers and fibrils, and the alarmin high-mobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-κB axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (Aβ(1-42) oligomers and HMGB-1) and pathways (RAGE/NF-κB activation) that also contribute to neuroinflammation/neurotoxicity. A more detailed analysis confirmed no significant increase of new mature neurons in hippocampi of TgCRND8 compared with WT mice, suggesting reduced survival and/or integration of newborn neurons. Therapeutic strategies in AD should ideally combine the ability of sustaining hippocampal neurogenesis as well as of counteracting an hostile brain microenvironment so to promote survival of vulnerable cell populations, including adult generated neurons.
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara 28100, Italy.
authors.forename: Vasco
authors.initials: V
authors.lastname: Meneghini
authors.forename: Valeria
authors.initials: V
authors.lastname: Bortolotto
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Francese
authors.forename: Anna
authors.initials: A
authors.lastname: Dellarole
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Carraro
authors.forename: Slavica
authors.initials: S
authors.lastname: Terzieva
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grilli
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D052002:NF-kappa B p50 Subunit; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C075222:amyloid beta-protein (1-42); D007770:L-Lactate Dehydrogenase; D001973:Bromodeoxyuridine
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