50

Bioinformatics of the Brain

2 (PSEN2) gene) cause familial AD (FAD) [41], sporadic (SAD) or late on-

set AD (LOAD) originates from environmental factors and various isoforms

and polymorphisms, particularly in the apolipoprotein E gene (APOE4), clus-

terin (CLU), complement receptor 1 (CR1), and phosphatidylinositol bind-

ing clathrin assembly protein (PICALM), bridging integrator 1 (BIN1), ATP

binding cassette transporter 7 (ABCA7), membrane-spanning 4-domains sub-

family A (MS4A), etc. [42, 43].

2.3.1.1

iPSCs and ESCs in AD Modeling

Recent advances in the field of induced pluripotent stem cells have enabled

patient- and disease-specific embryonic-like stem cells with the potency to give

several cell types, including AD-nervous system cells [44]. Hereby, iPSCs have

become prominent to be used for alternative approaches. For instance, the

iPSC-derived AD model has recently provided knowledge about the develop-

mental process and pathological progress of the disorder. Secondly, iPSCs are

promoted to differentiate into healthy neurons to substitute the patch of dead

brain tissue in vivo [45].

Chang et al. generated iPSCs from the FAD patients carrying a heterozy-

gous D678H mutation in the APP gene. After iPSCs were modeled into FAD-

neurons, they investigated the effects of this mutation on Aβ-tau pathology

and neurite formation. The study also revealed novel therapeutic targets and

the indole compound NC009-1 as a promising agent for rescuing AD pheno-

types [46]. Moore and colleagues examined the relationship between different

PSEN1/APP mutations and Aβ/tau accumulation in an iPSC-derived human

cerebral cortex model. They demonstrated that the APP mutation (V717I),

APP duplication, and multiple PSEN1 mutations (Y115C, M146I) altered

APP processing, resulting in increased extracellular Aβ production. The APP

V717I mutation and duplication also increased neuronal tau levels and phos-

phorylation. Besides, pharmacological inhibition of either γ- or β-secretase

alleviated extracellular Aβ peptides and tau levels with increased phosphory-

lation in cortical neurons of each genotype [47]. Kondo and coworkers recently

developed cellular dissection of polygenicity (CDiP) technology to unravel ge-

netic risk factors in sporadic Alzheimer’s disease (SAD) [48]. In this study,

researchers constituted 102 AD patient-derived iPSC lines. A genome-wide as-

sociation study (GWAS) in cortical neurons that originated from iPSCs came

up with 24 significant loci related to Aβ alterations. 11 of the 24 genes were as-

sociated with AD pathology for the first time. Additionally, their novel genetic

analysis method (CDiP) allowed the prediction of SAD onset and hallmarks

in clinical cohorts by combining GWAS iPSC-originated cells and machine

learning [48, 49]. Ghatak et al. composed a cerebrocortical organoid bearing

FAD-related mutations in presenilin-1 (δE9/WT, M146V/WT) and APP by

differentiating iPSCs to investigate early FAD pathophysiology and mecha-

nistic insights into hyperexcitability [50]. Remarkable evidence about the as-

sociation between low-density lipoprotein receptor-related protein 1 (LRP1)