Therapeutic Potential of Stem Cells in Neurodegenerative Diseases

51

and tau endocytosis and aggregation was uncovered by Rauch and coworkers.

Here, comprehensive analysis in iPSC-derived AD models identified LRP1 as

the main receptor that regulates tauopathy [51]. iPSCs and iPSC-originated

neuron models are not only convenient for investigating AD pathophysiology

but also outstanding for exploring the interaction and signaling processes be-

tween AD-neurons and microglia in a 3D microenvironment. There are also

several studies representing how microglial cell behaviors, such as phagocy-

tosis, lipogenesis, inflammatory responses, cytokine secretion, migration, and

viability, dramatically underwent alterations due to Aβ/tau pathology and

certain mutations related to SAD or FAD [52–56]. AD models were also cre-

ated at the cellular level by using human embryonic stem cells (hESCs). For

instance, mutant Presenilin1 (PSEN1 or PS1) was overexpressed in the hESC

line to recapitulate AD phenotypes. Upon neural differentiation, the electro-

physiological status of the synapses was extensively examined [57]. Similarly,

there are plenty of studies exploring cognitive functions, genetic factors, Aβ

pathophysiology, autophagy induction, neurotoxicity, and neurodegenerative

hallmarks in AD models that originated from either human or mouse ESCs

[58–62]. Furthermore, mouse ESCs are feasible to analyze the behaviors of

AD-related cellular models in vivo by engrafting into the mice bodies.

iPSCs stand as substantial vehicles for targeted gene therapies and

genome editing experimentation as well [45, 63]. As reported before, human

apolipoprotein E (APOE) was identified as the most effective and most com-

mon risk factor in AD cases. While the APOE4 isoform was associated with

a high risk for sporadic AD, APOE3 corresponds to a neutral risk of devel-

oping AD [64–68]. Several studies have demonstrated that the conversion of

the APOE4 allele to the APOE3 allele by gene editing techniques in human

iPSC-based neural models rescued the phenotypes of AD [69–72]. Trisomy 21

(Down syndrome) is known to deduce a propensity for early-onset AD due to

an increased dosage of the APP gene [73–75]. Intriguingly, APP copy number

was normalized via the CRISPR-Cas9 system in patient-derived iPSCs and

human embryonic stem cell lines (GeneA021 and GeneA022) to observe the

phenotypic effects of dosage compensation on Down syndrome-associated AD

pathogenesis [76], altogether suggesting genetically manipulated iPSC-derived

neurons could potentially ameliorate Aβ/tau pathophysiology-associated de-

mentia in individuals.

Together, these and more highlight the significance and usefulness of iPSCs

to interrogate the genetic events and molecular mechanisms in Alzheimer’s

disease.

2.3.1.2

iPSCs in Drug Screening for AD Modeling

iPSC-derived neural cells, 3D culture platforms, or organoids offer new ther-

apeutics for Alzheimer’s disease treatment before proceeding to preclinical

animal tests and clinical trials. Novel pharmacological molecules are gener-

ally tested to determine how promising they are to downgrade AD symptoms.