Delayed Dendritic Development in Newly Generated Dentate Granule Cells by Cell-Autonomous Expression of the Amyloid Precursor Protein

MORGENSTERN NA; GIACOMINI D; LOMBARDI G; CASTAÑO EM; SCHINDER AF

MOLECULAR AND CELLULAR NEUROSCIENCES.

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2013 vol. 56 p. 298 - 306

1044-7431

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 thecellular basis of cognitive decline that occurs during normal aging and in neurodegenerative disorders. Inthis work we have designed a novel approach to assess alterations in the dynamics of functional andstructural connectivity elicited by chronic cell-autonomous overexpression of the human amyloidprecursor protein (hAPP). We have taken advantage of the fact that the hippocampus continuouslygenerates new dentate granule cells (GCs) to probe morphofunctional development of GCs expressingdifferent variants of hAPP in a healthy background. hAPP was expressed together with a fluorescentreporter in neural progenitor cells of the dentate gyrus of juvenile mice by retroviral delivery. Neuronalprogeny was analyzed several days post infection (dpi). Amyloidogenic cleavage products of hAPP suchas the β-C terminal fragment (β-CTF) induced a substantial reduction in glutamatergic connectivity at 21dpi, at which time new GCs undergo active growth and synaptogenesis. Interestingly, this effect wastransient, since the strength of glutamatergic inputs was normal by 35 dpi. This delay in glutamatergicsynaptogenesis 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 nonamyloidogeniccleavage product of hAPP. These results indicate that hAPP can elicit protracted dendriticdevelopment independently of the amyloidogenic processing pathway