Center for the Biology of Disease 11

Leuven, Belgium

Center for the Biology of Disease 11

Leuven, Belgium
SEARCH FILTERS
Time filter
Source Type

Borgegard T.,Astrazeneca | Gustavsson S.,Astrazeneca | Nilsson C.,Astrazeneca | Parpal S.,Astrazeneca | And 28 more authors.
Journal of Neuroscience | Year: 2012

γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The y-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD. © 2012 the authors.


Salta E.,Catholic University of Leuven | Salta E.,Center for the Biology of Disease 11 | De Strooper B.,Catholic University of Leuven | De Strooper B.,Center for the Biology of Disease 11
The Lancet Neurology | Year: 2012

The importance of various classes of regulatory non-protein-coding RNA molecules (ncRNAs) in the normal functioning of the CNS is becoming increasingly evident. ncRNAs are involved in neuronal cell specification and patterning during development, but also in higher cognitive processes, such as structural plasticity and memory formation in the adult brain. We discuss advances in understanding of the function of ncRNAs in the CNS, with a focus on the potential involvement of specific species, such as microRNAs, endogenous small interfering RNAs, long intergenic non-coding RNAs, and natural antisense transcripts, in various neurodegenerative disorders. This emerging field is anticipated to profoundly affect clinical research, diagnosis, and therapy in neurology. © 2012 Elsevier Ltd.

Loading Center for the Biology of Disease 11 collaborators
Loading Center for the Biology of Disease 11 collaborators