an-vitro-model-for-studying-tau-aggregation-using-lentiviral-mediated

An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons

Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer&#8217;s disease (AD). ...

University of California, San Diego

The recent discovery of a simple method for making induced pluripotent stem cells (iPSC) from human somatic cells was a major scientific advancement that opened the way for many promising new developments in the study of developmental and degenerative diseases. iPSC have already been used to model many different types of neurological diseases, including autism, schizophrenia, Alzheimer's disease and Parkinson's disease. Because of their pluripotent property, iPSC offer the possibility of modeling human development in vitro. Their differentiation seems to follow the developmental timeline and obeys environmental cues. Clinically relevant phenotypes of neurodegenerative pathologies have also been observed using iPSC derived human neuronal cultures. Options for treatment are still some way off. Although some early research in mouse models has been encouraging, major obstacles remain for neural stem cell (NSC) transplantation therapy. However, iPSC now offer the prospect of an unlimited amount of human neurons or astrocytes for drug testing. The aim of this review is to summarize the recent progress in modeling neural development and neurological diseases using iPSC and to describe their applications for aging research and personalized medicine. 

Bioengineered stem cells in neural development and neurodegeneration research.

Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, which are associated with the pathological aggregation of tau protein into neurofibrillary tangles (NFT). Studies have characterized tau as a "prion-like" protein given its ability to form distinct, stable amyloid conformations capable of transcellular and multigenerational propagation in clonal fashion. It has been proposed that progression of tauopathy could be due to the prion-like propagation of tau, suggesting the possibility that end-stage pathologies, like NFT formation, may require an instigating event such as tau seeding. To investigate this, we applied a novel human induced pluripotent stem cell (hiPSC) system we have developed to serve as a human neuronal model. We introduced the tau repeat domain (tau-RD) with P301L and V337M (tau-RD-LM) mutations into hiPSC-derived neurons and observed expression of tau-RD at levels similar to total tau in postmortem AD brains. Tau aggregation occurred without the addition of recombinant tau fibrils. The conditioned media from tau-RD cultures contained tau-RD seeds, which were capable of inducing aggregate formation in homotypic mode in non-transduced recipient neuronal cultures. The resultant NFTs were thioflavin-positive, silver stain-positive, and assumed fibrillary appearance on transmission electron microscopy (TEM) with immunogold, which revealed paired helical filament 1 (PHF1)-positive NFTs, representing possible recruitment of endogenous tau in the aggregates. Functionally, expression of tau-RD caused neurotoxicity that manifested as axon retraction, synaptic density reduction, and enlargement of lysosomes. The results of our hiPSC study were reinforced by the observation that Tau-RD-LM is excreted in exosomes, which mediated the transfer of human tau to wild-type mouse neurons in vivo. Our hiPSC human neuronal system provides a model for further studies of tau aggregation and pathology as well as a means to study transcellular propagation and related neurodegenerative mechanisms.

Article	Year
Bioengineered stem cells in neural development and neurodegeneration research. Ageing research reviews\| PubMed ID: 23651546	2013
Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation. Neurobiology of disease\| PubMed ID: 28610892	2017

Shauna H. Yuan

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