Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer's disease iPSC-derived neurons and mice

Molecular and Cellular Neurosciences
Carlo CusulinChristoph Patsch

Abstract

In drug discovery, as well as in the study of disease biology, it is fundamental to develop models that recapitulate aspects of a disorder, in order to understand the pathology and test therapeutic approaches. Patient-derived induced pluripotent stem cells (iPSCs) offer the potential of obtaining tissue-specific cells with a given human genotype. Here we derived neural cultures from Alzheimer's disease patient iPSCs and characterized their response to three classes of compounds that reduce the production of Aβ42, a major driving force of this pathology. We characterized their effect on the cells, looking at Tau proteostasis and gene expression changes by RNAseq. β-secretase inhibitor and γ-secretase modulators left the transcriptional balance of the cells virtually unaffected, while γ-secretase inhibitors caused drastic gene expression changes due to Notch inhibition. We observed similar effects in vivo, treating mice with the same compound classes. Our results show that β-secretase inhibitors and γ-secretase modulators are attractive candidates for modulating Aβ production in Alzheimer's disease. Moreover, we demonstrate that the response to compounds obtained with iPSC-derived neurons is similar to the one observable in vivo.

Citations

Oct 31, 2020·Trends in Molecular Medicine·Svetlana Pasteuning-VuhmanR Jeroen Pasterkamp
May 1, 2021·International Journal of Molecular Sciences·Gabriele BonaventuraSebastiano Cavallaro

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Alzheimer's Disease: Tau & TDP-43

Alzheimer's disease is a neurodegenerative disease. This feed focuses on the underlying role of tau proteins and TAR DNA-binding protein 43, as well as other genetic factors, in Alzheimer's disease.

Alzheimer's Disease: Transcription

Impaired transcription is associated with the pathogenesis and progression of conditions such as Alzheimer's disease (AD). Here are the latest discoveries pertaining to transcription and AD.

Alzheimer's Disease: RNA Sequencing

RNA sequencing studies have shed light on the genetic and molecular mechanisms related to the pathophysiology of Alzheimer's disease (AD). This feed follows papers using RNA sequencing technologies in Alzheimer's research.