title: Cerebellin 4, a synaptic protein, enhances inhibitory activity and resistance of neurons to amyloid-β toxicity.
abstract: Imbalances between excitatory and inhibitory transmissions in the brain anticipate the neuronal damage and death that occur in the neurodegenerative diseases like Alzheimer's disease (AD). We previously showed that amyloid-β (Aß), a natural peptide involved in the onset and development of AD, counteracts the neurotrophic activity of the nerve growth factor (NGF) by dampening the γ-aminobutyric acid (GABA)ergic connectivity of cultured hippocampal neurons. Neuronal plasticity is partly controlled by the NGF-promoted expression of the homologue of enhancer-of-split 1 (Hes1), a transcription factor that regulates the formation of GABAergic synapses. We now show that Hes1 controls the expression of cerebellin 4 (Cbln4), a member of a small family of secreted synaptic proteins, and we present the evidence that Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections. Cbln4 immunoreactivity was found in the hippocampus, mostly in the dendrites and somata of pyramidal neurons. In the CA1, the hippocampal region where the first neurons degenerate in AD, Cbln4 immunoreactivity was associated with GABAergic synapses (detected by vesicular inhibitory amino acid transporter [VGAT] immunostaining), which appear to surround and embrace the somata of CA1 pyramidal neurons (basket cells). Moreover, significant decreases of Hes1, Cbln4, and VGAT immunoreactivities and messenger RNA expression were found in the hippocampus of a mouse model of AD. We also found that either the overexpression of Cbln4 in cultured hippocampal neurons or the application of recombinant Cbln4 to the cultures increased the number of GABAergic varicosities, rescuing neurons from Aß-induced death. In contrast, knockdown of Cbln4 gene in cultured neurons was followed by a large reduction of GABAergic connections. Such an effect was reverted by exogenously added Cbln4. These findings suggest a therapeutic potential for Cbln4 in the treatment of AD.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Seville, Spain.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Chacón
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Seville, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: del Marco
authors.affiliation: Departamento de Plasticidad Neuronal, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Arévalo
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Seville, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Domínguez-Giménez
authors.affiliation: Departamento de Plasticidad Neuronal, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: García-Segura
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Seville, Spain. Electronic address: alfredo.rodriguez@cabimer.es.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Rodríguez-Tébar
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002478:Cells, Cultured; D059330:GABAergic Neurons / Q000473:pathology* / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics; D011498:Protein Precursors / Q000502:physiology*; D000072056:Transcription Factor HES-1
chemical_list: D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C542343:cerebellin 4 precursor, mouse
keywords: Alzheimer's disease; Amyloid β; Cerebellin 4; Hes1; Hippocampus; NGF