Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes

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.

Translational potential of human brain organoids

“…Their results indicated that major hallmarks of AD‐associated pathological phenotypes, such as amyloid aggregation and tau hyperphosphorylation, could be sufficiently reproduced in organoids derived from familial AD (fAD) patients 44. Importantly, these phenotypes emerged after long‐term culture, with amyloid aggregation preceding tau pathology.…”

“…Raja et al explored iPSC‐derived forebrain organoids to model the Alzheimer's disease (AD) 44. Their results indicated that major hallmarks of AD‐associated pathological phenotypes, such as amyloid aggregation and tau hyperphosphorylation, could be sufficiently reproduced in organoids derived from familial AD (fAD) patients 44.…”

“…Likewise, neurodegenerative diseases may be studied if the organoids can be endowed with an aging phenotype. In this regard, it is encouraging that (1) a model of human midbrain organoids produced neuromelanin, a dark pigment found in adult midbrains, after 2 months of culture;33 (2) long‐term cultured AD iPSC‐based brain organoids recapitulated both A β and tau pathology in a sequential manner 44. Further development in incorporation of other relevant cell types60 and accelerating maturation and/or aging in a dish67 would be extremely exciting and important.…”

Three-dimensional neuronal cell culture: in pursuit of novel treatments for neurodegenerative disease

“…[37] Whereas the relatively scarce amount of literature on neuronal organoids is mainly focusing on neurodevelopmental phenomena, Raja et al have shown its potential to study neurodegeneration. [46] In this study, neural organoids were formed from induced pluripotent stem cells derived from Alzheimer's disease patients. This organoid model has shown to be robust, Figure 2.…”

Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the Aβ42-Treated Forebrain Spheroids Derived from Human Stem Cells

“…3,4,23–26 In this study, two neural differentiation paradigms from human iPS cells through three-dimensional (3D) spheroid formation were investigated to obtain a forebrain-dominant culture. The first type of spheroids used dual Smad inhibition followed by sonic Hedgehog (Shh) pathway inhibition to enrich cortical neurons.…”