ArticleNeurobiology of disease2015
Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.
Article in Neurobiology of disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- Chronic suppression of monoacylglycerol lipase restores adult neurogenesis in the septal but not the temporal DG in Ts65Dn mouse model of Down syndrome.Brain research bulletin · 2026Article
- Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome.Disease models & mechanisms · 2023Article
- The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease.Journal of Alzheimer's disease reports · 2023Review
- Primary cilia and ciliary signaling pathways in aging and age-related brain disorders.Neurobiology of disease · 2022Review
- The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives.Frontiers in cellular neuroscience · 2022Review
- Postnatal Cytoarchitecture and Neurochemical Hippocampal Dysfunction in Down Syndrome.Journal of clinical medicine · 2021Article
- The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome.Scientific reports · 2021Article
- Astrocytes in Down Syndrome Across the Lifespan.Frontiers in cellular neuroscience · 2021Review
- Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome.International journal of molecular sciences · 2020Review
- Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved.Neural regeneration research · 2019Article
- Timing of Treatment with the Flavonoid 7,8-DHF Critically Impacts on Its Effects on Learning and Memory in the Ts65Dn Mouse.Antioxidants (Basel, Switzerland) · 2019Article
- Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond.International journal of molecular sciences · 2018Review
- GABABrain structure & function · 2018Article
- Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome.Translational neurodegeneration · 2018Article
- Rodent models in Down syndrome research: impact and future opportunities.Disease models & mechanisms · 2017Review
- Targeting APP/AICD in Down syndrome.Oncotarget · 2017Article
- Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome.Neurobiology of disease · 2017Article
- Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability.Neurobiology of disease · 2017Article
- Modeling Fragile X syndrome in neurogenesis: An unexpected phenotype and a novel tool for future therapies.Neurogenesis (Austin, Tex.) · 2017Article
- Altered neurogenesis in mouse models of Alzheimer disease.Neurogenesis (Austin, Tex.) · 2017Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
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.
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