| First Author | Chen XQ | Year | 2024 |
| Journal | Ann Neurol | Volume | 96 |
| Issue | 2 | Pages | 390-404 |
| PubMed ID | 38747498 | Mgi Jnum | J:351617 |
| Mgi Id | MGI:7702373 | Doi | 10.1002/ana.26958 |
| Citation | Chen XQ, et al. (2024) gamma-Secretase Modulator BPN15606 Reduced Abeta42 and Abeta40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome. Ann Neurol 96(2):390-404 |
| abstractText | OBJECTIVES: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of gamma-secretase modulators that promote gamma-site cleavages by the gamma-secretase complex, resulting in lower levels of the Abeta42 and Abeta40 peptides. METHODS: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing gamma-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. RESULTS: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Abeta40 and Abeta42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-beta were not impacted, pointing to BPN15606-mediated enhancement of processivity of gamma-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. INTERPRETATION: Our findings point to the involvement of increased levels of Abeta42 and/or Abeta40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Abeta42 and/or Abeta40 as supporting pathogenesis. These findings further the interest in the potential use of gamma-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404. |
