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Bioinformatics of the Brain

Furthermore, candidate molecules can be evaluated for patient- or AD-type-

specific conditions owing to the production method from a unique starting

origin, that is, iPSC-based platforms enable the customization of drug screen-

ing studies.

A plant polyphenol, apigenin, was tested against neuroinflammation and

neurotoxicity in an iPSC-derived human AD model by Balez and cowork-

ers. When compared to healthy controls, apigenin could present neuropro-

tective activity in both SAD and FAD neurons by protecting iPSC-derived

neurons from inflammatory stress and reducing apoptosis and hyperexcitabil-

ity [77]. Another study by Yahata and colleagues exhibited a drug screening

platform targeting Aβ deposition through iPS-derived neurons. Various β-

/γ-secretase inhibitors, such as β-secretase inhibitor IV (BSI), γ-secretase

inhibitor XXI/Compound E (GSI), non-steroidal anti-inflammatory drug

(NSAID), and sulindac sulfide were found efficacious to modulate APP cleav-

age and Aβ production [78]. Similarly, β-secretase inhibitors were reported

to regulate glycogen synthase kinase 3 (GSK3) activity and, therefore, APP-

mediated tau phosphorylation in a 3D neural cell culture model with FAD

mutations [79]. Hossini et al. elicited the inhibitory effects of GSI against

Aβ/tau pathology through a GSK3B pathway in neurons differentiated from

SAD donor-originated iPSCs as well [80]. iPSC-based neural models also pro-

posed cholesterol metabolism as a druggable target to suppress hyperphos-

phorylation of tau protein. Screening a compound library composed of 1684

FDA-approved drugs revealed that cholesterol-lowering drugs reduced the

aberrant tau accumulation in iPSC-derived astrocytes and neurons through a

CYP46A1-Cholesterol Esters-Tau axis in Alzheimer’s disease [81]. Numerous

drug screening and drug repurposing platforms, including massive compound

libraries, are still under evaluation in iPSC-based models to combat Aβ/tau-

caused neurotoxicity and dementia in AD [82–87].

2.3.1.3

Pre-clinical or Clinical Trials of iPSCs and ESCs in AD

Due to the safety concerns about iPSCs and ethical/legal obstacles for human

ESCs, cell replacement therapy does not exist at clinical grade yet. How-

ever, numerous pre-clinical attempts with human iPSCs and ESCs for the

treatment of AD are still ongoing to monitor efficacy, molecular mechanisms,

and biological safety in regenerative applications. Human iPSC-derived neural

progenitor cells were transplanted into the hippocampus of AD mouse mod-

els in a study published in 2015. After transplantation, iPSC-derived neurons

could alleviate cognitive loss and dementia in mice by allowing the spread of

human-origin GABAergic neurons, choline acetyltransferase (ChAT)-positive

cholinergic neurons, and alpha7 nicotinic acetylcholine receptor (α7nAChR)-

positive neurons in the mouse cortex [88]. Recovery of spatial memory loss

in human APP-transgenic mice after grafting neuronal precursor cells derived

from human iPSCs was reported by Suzuki’s research group [89]. Armijo et al.

also demonstrated that the injection of mouse iPSC-derived neural precursors