Abstract
While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re-entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. Our endotype-centric screening approach offers a new paradigm by which candidate AD therapeutics can be evaluated for their overall ability to reverse disease endotypes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2117-2130 |
| Number of pages | 14 |
| Journal | Alzheimer's and Dementia |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2022 |
Bibliographical note
Funding Information:This study was supported by the Alzheimer's Association New Investigator Research Award (NIRG-14-322164) to S.H.Y.; NIH grants P50 AGO5131 (D.R.G), U01 NS 074501-05 (S.L.W), U01 AG048986 (S.L.W), R01 LM012595 (S.S.), U01 CA198941 (S.S.), U01 DK097430 (S.S.), R01 DK109365 (S.S.), R01 HD084633 (S.S.), and R01 HL108735 (S.S.); the National Science Foundation grant STC CCF-0939370 (S.S.); the Joan and Irwin Jacobs Endowment (S.S.); the Cure Alzheimer's Fund (CAF) grants to S.L.W. and R.E.T.; and the Veterans Affairs RR&D 1I01RX002259 (S.L.W.). S.L.W. and S.S. also acknowledge a grant from the D.H. Chen Foundation. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.
Funding Information:
This study was supported by the Alzheimer's Association New Investigator Research Award (NIRG‐14‐322164) to S.H.Y.; NIH grants P50 AGO5131 (D.R.G), U01 NS 074501‐05 (S.L.W), U01 AG048986 (S.L.W), R01 LM012595 (S.S.), U01 CA198941 (S.S.), U01 DK097430 (S.S.), R01 DK109365 (S.S.), R01 HD084633 (S.S.), and R01 HL108735 (S.S.); the National Science Foundation grant STC CCF‐0939370 (S.S.); the Joan and Irwin Jacobs Endowment (S.S.); the Cure Alzheimer's Fund (CAF) grants to S.L.W. and R.E.T.; and the Veterans Affairs RR&D 1I01RX002259 (S.L.W.). S.L.W. and S.S. also acknowledge a grant from the D.H. Chen Foundation. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.
Publisher Copyright:
Alzheimer's & Dementia© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Keywords
- Alzheimer's disease
- Alzheimer's therapy
- PSEN1
- RNA-seq
- disease endotypes
- drug profiling
- drug treatment
- early-onset Alzheimer's disease
- endotypes
- familial Alzheimer's disease
- gamma secretase
- iPSC-derived neurons
- iPSCs
- presenilin1
