Published in

Elsevier, Journal of Biological Chemistry, 29(288), p. 20817-20829, 2013

DOI: 10.1074/jbc.m113.451088

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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*

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 (sAPP). 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 over-expression of Patched1 (Ptch1), its inhibitory regulator. Ptch1 over-expression 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 over-expression 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, while the APP/sAPP system promotes astrogliogenesis through an IL-6-associated signaling cascade. These results provide novel insight into the mechanisms underlying brain development alterations in DS.