γ-Secretase generates the peptides of Alzheimer's disease, Aβ40 and Aβ42, by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ42/Aβ40 ratio, and are thus a promising therapeutic approach for Alzheimer's disease. However, the target for γ-secretase modulators is uncertain, with some data suggesting that they function on γ-secretase, whereas others support their binding to the amyloid precursor. In this paper we address this controversy by using a fluorescence resonance energy transfer-based assay to examine whether γ-secretase modulators alter Presenilin-1/γ-secretase conformation in intact cells in the absence of its natural substrates such as amyloid precursor protein and Notch. We report that the γ-secretase allosteric site is located within the γ-secretase complex, but substrate docking is needed for γ-secretase modulators to access this site.
BackgroundSeveral familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.ResultsBy using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ42/40 ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation.ConclusionsThus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.
BackgroundContraceptive counseling can increase postpartum contraception use, yet the optimal method and timing for counseling are unknown. The objective was to investigate preferences of underserved pregnant and postpartum women regarding contraception use and counseling.MethodSurveys regarding contraception experiences and perceptions of contraceptive counseling were conducted with 57 women age 18 and older who were postpartum or antepartum with a previous delivery within 5 years and receiving Medicaid-funded care at an academic medical center. Health literacy was assessed using REALM-7. Responses were analyzed using descriptive statistics.ResultsA majority of women reported unplanned pregnancies (78%). Women using contraception at the time of conception reported “not sure” (30%) and “taken wrong” (30%) as primary reasons for failure. Most subjects had at least a high school level of health literacy (88%), desired to use a postpartum contraceptive method (92%) and had a high self-reported understanding of that method (94%). Most women reported receiving counseling (91%) and stated that the best time for counseling was both before and after childbirth (84%). However, only 60% of subjects intended to use the method they were prescribed at discharge; reasons for changing included side effects (37%), desire for different contraception (23%) and too complicated of a method prescribed (17%).ConclusionWomen perceived the best timing of contraceptive education to be both antepartum and postpartum. Despite a high frequency of prior contraceptive failure, self-reported understanding of the chosen postpartum contraceptive method was high. Contraception counseling should be tailored to a woman’s perceived needs, with such education occurring frequently and within the context of her health literacy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.