Abstract
The dismal success rate of clinical trials for Alzheimer’s disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments, which has become the sixth leading cause of death in the United States [1,2]
In diseases such as AD that are characterized by protein aggregation, the presence of a true interstitial compartment is important for modeling pathology
Previous three-dimensional (3D) tissue engineering approaches have embedded neural progenitors or cell types of interest in a matrix or a scaffold [40,58]. While these ingenious approaches can model AD phenotypes, they do not recapitulate spontaneous pathology resulting from endogenous cellular characteristics, but rather necessitate the overexpression of familial AD (fAD) genes
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments, which has become the sixth leading cause of death in the United States (www.alz.org) [1,2]. The advent of induced pluripotent stem cells (iPSCs) has revolutionized human in vitro models systems [34,35,36,37] Using this technology, we can derive specific neural cell types from patients with sporadic or familial AD, and use these cultures to both study disease mechanisms and develop novel therapies [38,39]. After twelve weeks in vitro, these cultures generated AD-like phenotypes including amyloid plaque deposition and hyperphosphorylated tau [40,58] Another group studied AD-relevant phenotypes in scaffolded 3D culture systems following exogenous amyloid β (Aβ) application [59]. We have adapted a scaffold-free culture approach to generate neural organoids from AD patient derived cells These 3D cultures efficiently produce robust AD phenotypes, without genetic manipulation or exogenous toxins. We demonstrate that this model system is amenable to experimental manipulation, such as drug treatment, and that these phenotypes are robust enough to be recapitulated across multiple cells lines derived from different AD patients
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