title: Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.
abstract: Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacomini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Stagni
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guidi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Emili
authors.affiliation: Elan Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brigham
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address: renata.bartesaghi@unibo.it.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D018696:Neuroprotective Agents; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011720:Pyrazoles; D011804:Quinolines; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; C573127:(R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline; D053829:Amyloid Precursor Protein Secretases
keywords: AICD; APP; Down syndrome; Neonatal pharmacotherapy; γ-Secretase