Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice

Abstract

␥-Secretase inhibitors (GSIs) reduce amyloid-␤ (A␤) peptides but inevitably increase the ␤-C-terminal fragment (␤-CTFSubchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other ␥-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with ␤-CTF accumulation. Immunofluorescence studies revealed that the ␤-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.

The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor

“…In addition, the protein degradation activities of proteasomes, lysosomes and autophagy gradually decline with age and contribute to high levels of APP-CTFb and Ab, and consequently to an increased risk of sporadic AD 7,8,45 . On the other hand, clinical trials using non-selective inhibitors of g-secretase activity were discontinued due to adverse effects that were probably caused by Notch inhibition and APP-CTF accumulation [11][12][13]55 . Thus, ILEI may be a plausible target for the development of diseasemodifying therapies for AD, because ILEI may alter disease progression without perturbing Notch signalling and increasing APP-CTFb.…”

“…Although g-secretase is a major target for therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signalling and accumulation of neurotoxic APP-CTFs 1,[11][12][13] . To avoid these adverse effects, finding novel approaches to negatively modulate Ab generation is imperative.…”

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

“…A range of Notch/Ab IC 50 ratios have been reported for avagacestat, from as low as 2.9 to as high as 193 (Martone et al, 2009;Gillman et al, 2010;Chávez-Guttiérez et al, 2012;Crump et al, 2012;Mitani et al, 2012) (Supplemental Table 1). This range is partly due to differences in methodology, such as cell-based formats or choice of enzymatic assays, and partly due to the increased potency of GSIs when substrate expression levels are higher (Burton et al, 2008).…”

APP mouse models for Alzheimer's disease preclinical studies

“…Overproduced non‐Aβ APP fragments may interact unphysiologically with cellular proteins (Chang & Suh, 2005; Mitani et al , 2012; Nicolas & Hassan, 2014; Kerridge et al , 2015; Nhan et al , 2015; Willem et al , 2015; Xia et al , 2016). See Fig 3.…”