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.

Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome

“…In contrast, immediately after the end of treatment Ts65Dn mice had a significantly larger number of both SYN and PSD-95 immunoreactive puncta (Giacomini et al, 2015). These results show that the restoration of connectivity observed in the DG of P15 mice at the end of treatment does not outlive treatment cessation and suggests that continuous treatment may be necessary in order to maintain this effect.…”

Altered neurogenesis in mouse models of Alzheimer disease

“…43 In support of this observation, a recent study has been demonstrated that g-secretase inhibitor treatment normalized AICD levels and restored impaired neurogenesis and Sonic Hedgehog signaling in Ts65Dn-derived neurospheres. 50 The crucial role of AICD is underscored by an agedependent decrease in BrdU incorporation and DCX-immunoreactive cells in the dentate gyrus of AICD transgenic mice. While neuronal differentiation was unaffected, proliferation and survival of progenitor cells was strongly reduced.…”

Sonic Hedgehog Signaling and Hippocampal Neuroplasticity

“…Treatment of newborn Ts65Dn mice, a mouse model of DS, with the Shh pathway agonist SAG ameliorates cerebellar development defects, effectively restoring the granule cell precursor pool [49]. Hippocampal neurogenesis is impaired in Ts65Dn mice, a model of Down syndrome, and neurogenesis is normalized when the mice are treated with a γ-secretase inhibitor [51]. Shh signaling is required for restoration of neurogenesis because inhibition of γ-secretase does not restore neurogenesis when mice are treated with cyclopamine.…”