Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy

Abstract

␥-Secretase inhibition represents a major therapeutic strategy for lowering amyloid ␤ (A␤) peptide production in Alzheimer's disease (AD).Progress toward clinical use of ␥-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The ␥-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A␤ 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 ␥-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 A␤ 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 ␥-secretase targeting strategy for AD.

Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter β‐amyloid levels in the CNS

“…Bioanalysis of plasma and brain homogenate samples was performed as previously described (Borgegård et al . ). Briefly, the right brain hemisphere was homogenized in two volumes (w/v) of Ringer solution using a multi‐element sonication probe.…”

γ-Secretase inhibitors and modulators

“…Zhao and colleagues have shown that sulfonamide based GSIs selectively inhibit PSEN1 over PSEN2, whereas the GSIs DAPT and L685458 showed minimal selectivity [105]. Similarly, recent data suggest that the GSI MRK-560 preferentially targets PSEN1 over PSEN2 and that this selectivity, at least in mice, increases the tolerability of this GSI [106]. De Strooper and colleagues also show that heterogeneity with respect to the Aph1 subunit is important with respect to viability and overall phenotype of mice, indicating that selective targeting of Aph1b γ-secretase complexes may be less toxic [107]; however, it is not clear whether selective targeting of Aph1b γ-secretase complexes is feasible.…”

Signature Amyloid β Profiles Are Produced by Different γ-Secretase Complexes

“…But, interestingly, PSEN2 containing ␥-secretase complexes appear to carry out an important part of the physiological processing of Notch in peripheral organs. The differential activity profiles of PSEN1/2 complexes were actually exploited in a study conducted by Borgegård et al (30) in which in vivo inhibition of APP processing by a PSEN2-sparing ␥-secretase inhibitor (MRK-560) circumvented to a large extent Notch-related side effects. These results demonstrate that PSEN1 and PSEN2 ␥-secretase complexes can be targeted specifically and provide the first preclinical proof of concept that differential targeting of ␥-secretase complexes is a worthwhile strategy in therapy development for AD.…”