Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies

Abstract

Summary The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.

The Role of Neurod Genes in Brain Development, Function, and Disease

“…These results provide a potential therapeutic approach to patients affected with Alzheimer’s disease. The half-life of Neurod1 can be increased by blocking its ubiquitin-dependent proteasomal degradation, which enhances the transcriptional programs mediated by Neurod1 during neuronal differentiation, but also those involved in neuronal maturation and synaptic transmission (de Wilde et al, 2016 ; Lee et al, 2020 ; Pomeshchik et al, 2020 ). Neurod1 has also been used to successfully reprogram reactive glial cells functional cortical neurons in stab-injured or Alzheimer’s disease mouse models and in adult non-human primates after ischemic stroke, which again offers the possibility to develop new therapeutical approaches for patients affected with Alzheimer’s disease (Guo et al, 2014 ; Ge et al, 2020 ).…”

TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

“…The authors declare no competing interests iPSC line derivation and production of astrocytes iPSC generation for CSC-9A, CSC-10A/B/C, CSC-7A/B, CSC-21B, CSC-18A, CSC-19A, and CSC-3G/S was previously published (Holmqvist et al, 2016). The same procedure was used to reprogram human epidermal fibroblasts, harvested using a skin punch biopsy from healthy donors CSC-36D and CSC-37R (Pomeshchik et al, 2020), a PD patient with a SNCA gene triplication CSC-28N (parent fibroblasts were previously employed to generate the lines CSC-3G and À3S), and two PD patients with idiopathic PD CSC-26B (59 year old female) and CSC-27I/K (47 year old male). In this study, astrocytes were generated from 74 differentiations in total, all started from pluripotent stem cell stage, from 17 iPSC clones (2-3 clones per donor group) generated from 9 familial and idiopathic PD patients, and 2 healthy individuals.…”

Expression of Endogenous Angiotensin-Converting Enzyme 2 in Human Induced Pluripotent Stem Cell-Derived Retinal Organoids

“…Induced pluripotent stem cell (iPSC) technologies and patient-derived iPSCs provide opportunities for regenerative medicine, drug discovery, and disease modeling from patient-derived stem cells, such as in cystic fibrosis, Huntington’s, Duchenne muscular dystrophy, Alzheimer, amyotrophic lateral sclerosis, age macular degeneration, and retinitis pigmentosa [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Although monolayer cultures are relatively easy to be cultivated, the features that they do not display, the complex tissue organization, limits their bioavailability.…”