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

Abstract

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.

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

“…7c - d ). Our results are in line with previous studies showing reduced levels of synaptic protein in Ts65Dn mice and their induction after disease-modifying treatment leading to improved cognition [ 67 – 69 ]. Intriguingly, the two-way anova analyses of PSD95 show indeed that the treatment account for the 37.7% ( p = 0.0077) of the total variance.…”

“…As well, the NOR test showed the improvement of mice preference index supporting the recovery of novelty-discriminating ability after rapamycin administration. Further, we suggest that the improved cognition, exerted by InRapa, is associated with the rescue of synaptic abnormalities previously observed in DS [ 60 , 69 ]. Therefore, as previously proven in AD, our data support the capability of rapamycin, if delivered chronically and intranasally before consistent brain damage, to improve memory and reduce cognitive decline in DS mice [ 31 ].…”

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

“…Elevated spiking rates of pyramidal neurons in Ts65Dn mice may have been reflected in larger theta and gamma oscillations in the PFC and HPC (32). Increased excitability of pyramidal neurons has been associated with premature aging in Ts65Dn mice (50,51), as these mice show early-onset Alzheimer's disease after 6 months of age. Here we discard premature aging as a main factor because the quantification of firing rates was performed in 3-month-old TS mice.…”

Gamma secretase inhibitors inhibit ovarian cancer development and enhance olaparib’s anti-ovarian cancer activity and its mechanism

“…It was originally discovered that the deletion of this gene can lead to notches in the wings of Drosophila, and hence its name, participating in the maintenance of cell homeostasis is a relatively conservative signaling pathway. In mammals, the Notch signaling pathway includes four receptors and five ligands, of which Jagged1 is an important downstream molecule of the signaling pathway, and its expression is increased in many solid tumors such as lung cancer, cervical cancer, colon cancer and kidney cancer,and through the excessive activation of Notch1 / Jagged1 in malignant tumor tissue to promote cell proliferation and invasion [30][31][32] . The results of this study show that DAPT treatment can significantly inhibit the expression and transcription of Jagged1, and gene knockout experiments further indicate that Jagged1 may be a potential downstream target of DAPT tumor suppressor activity.…”