Importance: Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells.
Objective: To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L).
Design, Setting, And Participants: Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures.
Main Outcomes And Measures: Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay.
Results: As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels.
Conclusions And Relevance: This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.
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http://dx.doi.org/10.1001/jamaneurol.2014.2482 | DOI Listing |
Methods Mol Biol
December 2024
Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil.
This chapter presents an optimized method for isolating synaptic vesicles (SVs) from neurospheres derived from human induced pluripotent stem cells (hiPSCs). The protocol begins with neurosphere cultivation to achieve mature neurons, which is essential for the functional studies of neuronal activity. Following this, neurosphere-derived synaptosomes are isolated, and SVs are enriched through differential centrifugation.
View Article and Find Full Text PDFMetab Brain Dis
December 2024
Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Traumatic brain injury (TBI) is a significant contributor to global mortality and morbidity, with emerging evidence indicating a heightened risk of developing Alzheimer's disease (AD) following TBI. This study aimed to explore the molecular intersections between TBI and AD, focusing on the role of adipose mesenchymal stem cell (ADMSC)-derived exosomes and hub genes involved in microglial polarization. Transcriptome profiles from TBI (GSE58485) and AD (GSE74614) datasets were analyzed to identify differentially expressed genes (DEGs).
View Article and Find Full Text PDFJ Med Genet
December 2024
Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.
Background: Previous studies in mouse, and zebrafish embryos show strong expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 ( in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.
Methods: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies.
Neural Regen Res
November 2025
Department of Neuroscience, Ohio State University, Columbus, OH, USA.
In recent years, the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine. Considering the non-regenerative nature of the mature central nervous system, the concept that "blank" cells could be reprogrammed and functionally integrated into host neural networks remained intriguing. Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells, such as neurons.
View Article and Find Full Text PDFMethods Mol Biol
December 2024
Department of Experimental Medicine, Biotechnology, and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy.
Mesenchymal stromal cells (MSCs) are a heterogeneous population of non-hematopoietic adult stem cells derived from the embryonic mesoderm. They possess self-renewal and multipotent differentiation capabilities, allowing them to give rise to mesodermal cell types, such as osteoblasts, chondroblasts, and adipocytes, as well as non-mesodermal cells, including neuron-like cells and endothelial cells. MSCs play a vital role in maintaining homeostasis across various tissues by facilitating tissue repair, immune regulation, and inflammatory response balance.
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