title: The amyloid precursor protein (APP) triplicated gene impairs neuronal precursor differentiation and neurite development through two different domains in the Ts65Dn mouse model for Down syndrome.
abstract: Intellectual disability in Down syndrome (DS) appears to be related to severe proliferation impairment during brain development. Recent evidence shows that it is not only cellular proliferation that is heavily compromised in DS, but also cell fate specification and dendritic maturation. The amyloid precursor protein (APP), a gene that is triplicated in DS, plays a key role in normal brain development by influencing neural precursor cell proliferation, cell fate specification, and neuronal maturation. APP influences these processes via two separate domains, the APP intracellular domain (AICD) and the soluble secreted APP. We recently found that the proliferation impairment of neuronal precursors (NPCs) from the Ts65Dn mouse model for DS was caused by derangement of the Shh pathway due to overexpression of patched1(Ptch1), its inhibitory regulator. Ptch1 overexpression was related to increased levels within the APP/AICD system. The overall goal of this study was to determine whether APP contributes to neurogenesis impairment in DS by influencing in addition to proliferation, cell fate specification, and neurite development. We found that normalization of APP expression restored the reduced neuronogenesis, the increased astrogliogenesis, and the reduced neurite length of trisomic NPCs, indicating that APP overexpression underpins all aspects of neurogenesis impairment. Moreover, we found that two different domains of APP impair neuronal differentiation and maturation in trisomic NPCs. The APP/AICD system regulates neuronogenesis and neurite length through the Shh pathway, whereas the APP/secreted AP system promotes astrogliogenesis through an IL-6-associated signaling cascade. These results provide novel insight into the mechanisms underlying brain development alterations in DS.
authors.affiliation: From the Department of Biomedical and Neuromotor Sciences and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.affiliation: From the Department of Biomedical and Neuromotor Sciences and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuchs
authors.affiliation: the Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy and.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valli
authors.affiliation: the Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy and; the Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Ozzano dell'Emilia, 40064 Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: From the Department of Biomedical and Neuromotor Sciences and.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
authors.affiliation: From the Department of Biomedical and Neuromotor Sciences and. Electronic address: elisabetta.ciani@unibo.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D048430:Cell Shape; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014314:Trisomy / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053823:Hedgehog Proteins; D015850:Interleukin-6; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse
keywords: APP; Astrogliogenesis; Cell Culture; Down Syndrome; Neurite Outgrowth; Neurobiology; Neurodevelopment; Neurogenesis; Neuroprogenitor Cell