Dataset Information

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

ABSTRACT: Traditional approaches to studying Alzheimer's disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased A?42 and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening.

SUBMITTER: Schrank S

PROVIDER: S-EPMC7037274 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

Schrank Sean S McDaid John J Briggs Clark A CA Mustaly-Kalimi Sarah S Brinks Deanna D Houcek Aiden A Singer Oded O Bottero Virginie V Marr Robert A RA Stutzmann Grace E GE

International journal of molecular sciences 20200204 3

Traditional approaches to studying Alzheimer's disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autono ...[more]

PMID: 32033164

Similar Datasets

Project description:Alzheimer's disease (AD), a neurodegenerative disorder that can occur in middle or old age, is characterized by memory loss, a continuous decline in thinking, behavioral and social skills that affect the ability of an individual to function independently. It is divided into sporadic and familial subtypes. Early-onset familial AD (FAD) is linked to mutations in genes coding for the amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2), which lead to alterations in AβPP processing, generation of the Amyloid-β peptide and hyperphosphorylation of tau protein. Identification of early biomarkers for AD diagnosis represents a challenge, and it has been suggested that molecular changes in neurodegenerative pathways identified in the brain of AD patients can be detected in peripheral non-neural cells derived from familial or sporadic AD patients. In the present study, we determined the protein expression, the proteomic and in silico characterization of skin fibroblasts from FAD patients with PS1 mutations (M146L or A246E) or from healthy individuals. Our results shown that fibroblasts from AD patients had increased expression of the autophagy markers LC3II, LAMP2 and Cathepsin D, a significant increase in total GSK3, phosphorylated ERK1/2 (Thr202/Tyr204) and phosphorylated tau (Thr231, Ser396, and Ser404), but no difference in the phosphorylation of Akt (Ser473) or the α (Ser21) and β (Ser9) GSK3 isoforms, highlighting the relevant role of abnormal protein post-translational modifications in age-related neurodegenerative diseases, such as AD. Both 2-DE gels and mass spectrometry showed significant differences in the expression of the signaling pathways associated with protein folding and the autophagic pathway mediated by chaperones with the expression of HSPA5, HSPE1, HSPD1, HSP90AA1, and HSPE1 and reticular stress in the FAD samples. Furthermore, expression of the heat shock proteins HSP90 and HSP70 was significantly higher in the cells from AD patients as confirmed by Western blot. Taken together our results indicate that fibroblasts from patients with FAD-PS1 present alterations in signaling pathways related to cellular stress, autophagy, lysosomes, and tau phosphorylation. Fibroblasts can therefore be useful in modeling pathways related to neurodegeneration, as well as for the identification of early AD biomarkers.

Project description: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 ?-secretase inhibitor and ?-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 ?-secretase inhibitor or GSM. Comparisons of total ?-amyloid (A?) and A? peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures. MAIN OUTCOMES AND MEASURES:Soluble A? levels in the media were measured by enzyme-linked immunosorbent assay. RESULTS:As predicted, mutant PS1 neurons exhibited an elevated A?42:A?40 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 A?42, A?40, and A?38 and in the A?42:A?40 ratio, with no change in the total A? 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.

Dataset Information

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

Publications

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets