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

Trazzi, Stefania; Fuchs, Claudia; Valli, Emanuele; Perini, Giovanni; Bartesaghi, Renata; Ciani, Elisabetta

doi:10.1074/jbc.m113.451088

Cited by 46 publications

(46 citation statements)

References 57 publications

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“…In a Ts65Dn mouse model of DS, it was demonstrated that the amyloid precursor protein (APP) triplicated gene impairs proliferation of NPCs from SVZ in the hippocampus [85,86] because high levels of the intracellular domain from APP cleavage by γ-secretase can raise the transcription of Ptch1, which is known to repress Shh pathway [85,86]. ELND006 is an inhibitor of γ-secretase that restores the Shh pathway and fully recovers the impaired neurogenesis in Ts65Dn pups [87].…”

Section: Sonic Hedgehog and Neurogenesis In Neurological Diseasesmentioning

confidence: 99%

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

Chen

Yang

Hwang

et al. 2018

IJMS

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Sonic hedgehog (Shh), a member of the hedgehog (Hh) family, was originally recognized as a morphogen possessing critical characters for neural development during embryogenesis. Recently, however, Shh has emerged as an important modulator in adult neural tissues through different mechanisms such as neurogenesis, anti-oxidation, anti-inflammation, and autophagy. Therefore, Shh may potentially have clinical application in neurodegenerative diseases and brain injuries. In this article, we present some examples, including ours, to show different aspects of Shh signaling and how Shh agonists or mimetics are used to alter the neuronal fates in various disease models, both in vitro and in vivo. Other potential mechanisms that are discussed include alteration of mitochondrial function and anti-aging effect; both are critical for age-related neurodegenerative diseases. A thorough understanding of the protective mechanisms elicited by Shh may provide a rationale to design innovative therapeutic regimens for various neurodegenerative diseases.

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Section: Sonic Hedgehog and Neurogenesis In Neurological Diseasesmentioning

confidence: 99%

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

Chen

Yang

Hwang

et al. 2018

IJMS

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“…APP affects neural precursor cell proliferation, cell fate, and maturation of neurons, as well as gliogenesis [98, 150]. There are both intracellular and secreted domains of APP that appear to play a role for brain development [151].…”

Section: Amyloid and Tau Pathologymentioning

confidence: 99%

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

Hamlett¹,

Boger²,

Ledreux³

et al. 2015

CAR

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Down syndrome (DS) is the most common non-lethal genetic condition that affects approximately 1 in 700 births in the United States of America. DS is characterized by complete or segmental chromosome 21 trisomy, which leads to variable intellectual disabilities, progressive memory loss, and accelerated neurodegeneration with age. During the last three decades, people with DS have experienced a doubling of life expectancy due to progress in treatment of medical comorbidities, which has allowed this population to reach the age when they develop early onset Alzheimer’s disease (AD). Individuals with DS develop cognitive and pathological hallmarks of AD in their fourth or fifth decade, and are currently lacking successful prevention or treatment options for dementia. The profound memory deficits associated with DS-related AD (DS-AD) have been associated with degeneration of several neuronal populations, but mechanisms of neurodegeneration are largely unexplored. The most successful animal model for DS is the Ts65Dn mouse, but several new models have also been developed. In the current review, we discuss recent findings and potential treatment options for the management of memory loss and AD neuropathology in DS mouse models. We also review age-related neuropathology, and recent findings from neuroimaging studies. The validation of appropriate DS mouse models that mimic neurodegeneration and memory loss in humans with DS can be valuable in the study of novel preventative and treatment interventions, and may be helpful in pinpointing gene-gene interactions as well as specific gene segments involved in neurodegeneration.

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“…This alteration can be ascribed to a cascade of events stemming from amyloid precursor protein (APP) triplication and culminating into overexpression of Patched 1 (Ptch1), the repressor of this pathway (Trazzi et al, 2011, Trazzi et al, 2013). In particular, cleavage of the APP-derived carboxy-terminal fragments (CTFs) by the enzyme gamma-secretase gives origin to the amyloid precursor protein intracellular domain (AICD) and either p3 or beta-amyloid (Abeta).…”

Section: Introductionmentioning

confidence: 99%

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

Stagni

Raspanti

Giacomini

et al. 2017

Neurobiology of Disease

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Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~ one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS.

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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

Cited by 46 publications

References 57 publications

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

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

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