title: Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein.
abstract: Neuronal connectivity and synaptic remodeling are fundamental substrates for higher brain functions. Understanding their dynamics in the mammalian allocortex emerges as a critical step to tackle the cellular basis of cognitive decline that occurs during normal aging and in neurodegenerative disorders. In this work we have designed a novel approach to assess alterations in the dynamics of functional and structural connectivity elicited by chronic cell-autonomous overexpression of the human amyloid precursor protein (hAPP). We have taken advantage of the fact that the hippocampus continuously generates new dentate granule cells (GCs) to probe morphofunctional development of GCs expressing different variants of hAPP in a healthy background. hAPP was expressed together with a fluorescent reporter in neural progenitor cells of the dentate gyrus of juvenile mice by retroviral delivery. Neuronal progeny was analyzed several days post infection (dpi). Amyloidogenic cleavage products of hAPP such as the β-C terminal fragment (β-CTF) induced a substantial reduction in glutamatergic connectivity at 21 dpi, at which time new GCs undergo active growth and synaptogenesis. Interestingly, this effect was transient, since the strength of glutamatergic inputs was normal by 35 dpi. This delay in glutamatergic synaptogenesis was paralleled by a decrease in dendritic length with no changes in spine density, consistent with a protracted dendritic development without alterations in synapse formation. Finally, similar defects in newborn GC development were observed by overexpression of α-CTF, a non-amyloidogenic cleavage product of hAPP. These results indicate that hAPP can elicit protracted dendritic development independently of the amyloidogenic processing pathway.
authors.affiliation: Laboratory of Neuronal Plasticity Leloir Institute (IIBBA-CONICET) Buenos Aires (1405), Argentina.
authors.forename: Nicolás A
authors.initials: NA
authors.lastname: Morgenstern
authors.affiliation: Laboratory of Neuronal Plasticity Leloir Institute (IIBBA-CONICET) Buenos Aires (1405), Argentina.
authors.forename: Damiana
authors.initials: D
authors.lastname: Giacomini
authors.affiliation: Laboratory of Neuronal Plasticity Leloir Institute (IIBBA-CONICET) Buenos Aires (1405), Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lombardi
authors.affiliation: Laboratory of Amyloidosis and Neurodegeneration Leloir Institute (IIBBA-CONICET) Buenos Aires (1405), Argentina.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
authors.affiliation: Laboratory of Neuronal Plasticity Leloir Institute (IIBBA-CONICET) Buenos Aires (1405), Argentina.
authors.forename: Alejandro F
authors.initials: AF
authors.lastname: Schinder
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003712:Dendrites / Q000378:metabolism* / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D055495:Neurogenesis; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: C-terminal fragment of APP; CTF; Dentate gyrus; Dpi; EPSC; GC; Neurodegeneration; Neuronal maturation; Synaptic transmission; Synaptogenesis; days post infection; dentate granule cell; excitatory postsynaptic current; hAPP; human Amyloid Precursor Protein; sEPSC; spontaneous excitatory postsynaptic current