1. 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.
- Author
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Meneghini V, Bortolotto V, Francese MT, Dellarole A, Carraro L, Terzieva S, and Grilli M
- Subjects
- Adult Stem Cells drug effects, Adult Stem Cells physiology, Age Factors, Amyloid beta-Protein Precursor genetics, Analysis of Variance, Animals, Animals, Newborn, Bromodeoxyuridine, Cell Death drug effects, Cell Death genetics, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, L-Lactate Dehydrogenase metabolism, Male, Mice, Mice, Transgenic, Mutation genetics, NF-kappa B p50 Subunit deficiency, Nerve Tissue Proteins metabolism, Neurons drug effects, Neurons physiology, SOXB1 Transcription Factors metabolism, Signal Transduction drug effects, Amyloid beta-Peptides pharmacology, Cell Differentiation drug effects, Glycation End Products, Advanced metabolism, HMGB1 Protein pharmacology, Hippocampus cytology, NF-kappa B p50 Subunit metabolism, Peptide Fragments pharmacology
- 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.
- Published
- 2013
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