Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease. Issue 11 (27th January 2022)

• Record Type: Journal Article
• Authors: Caldwell, Andrew B.; Liu, Qing; Zhang, Can; Schroth, Gary P.; Galasko, Douglas R.; Rynearson, Kevin D.; Tanzi, Rudolph E.; Yuan, Shauna H.; Wagner, Steven L.; Subramaniam, Shankar
• Is Part Of: Alzheimer's & dementia. Volume 18:Issue 11(2022)
• Page Start: 2117
• Page End: 2130
• Publication Date: 2022-01-27
• Subjects: Alzheimer's disease -- Alzheimer's therapy -- disease endotypes -- drug profiling -- drug treatment -- early‐onset Alzheimer's disease -- endotypes -- familial Alzheimer's disease -- gamma secretase -- iPSC‐derived neurons -- iPSCs -- presenilin1 -- PSEN1 -- RNA‐seq; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.12553
• Languages: English
• ISSNs: 1552-5260

Abstract

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 PSEN1 A246E 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. Abstract : Endotype screening for drug evaluation in Alzheimer's disease Conceptual overview of endotype screening for drug evaluation in Alzheimer's disease. (A) Stage 1: iPSCs are generated from healthy donors and familial Alzheimer's disease (FAD) patients and differentiated into neurons. RNA‐seq followed by differential gene expression (DGE), enrichment analysis, and ontological module detection leads to the identification of disease‐associated endotypes. (B) Stage 2: Transcriptomic reversal of FAD endotypes as a metric to evaluate candidate drug efficacy. (C) Overall mechanism, where Gamma‐secretase targeting drugs GSI and GSM differentially modulate PSEN1 A246E ‐induced disease endotpyes to drive cells back towards a more differentiated state.