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Precis Future Med > Volume 8(3); 2024 > Article |
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Sang Won Seo has been editorial board of Precision and Future Medicine since December 2017. He was not involved in the review process of this review article. No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: SL, HJK.
Acquisition, interpretation of data: SL, HJK.
Drafting the work or revising: SL, HJS, HJK.
Final approval of the manuscript: SL, HJS, SWS, DLN, HJK.
Disease | Gene mutations | Differentiated cell type | Application | Major findings | Reference |
---|---|---|---|---|---|
AD | APP (V171I) PSEN1 (int4del, Y115H, M139V, M146I, R278I) | Neuron | Disease modeling | Supported Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modeling fAD | [2] |
AD | PSEN1 (∆E9) | Astrocyte | Disease modeling | Increased oxidative stress | [3] |
Reduced lactate secretion | |||||
Role of astrocytes in AD pathology, including changes in neuron-supportive function | |||||
AD | PSEN2 (N141I) | Basal forebrain cholinergic neurons | Disease modeling | Defective electrophysiological properties | [4] |
AD | APP (V717I) | Neuron | Disease modeling | Increased Aβ42 and Aβ38 | [5] |
Increased total and phosphorylated tau | |||||
AD | PSEN1 (M146L, A246E) | Neural progenitor cells | Disease modeling | Increased in ABβ42/40 peptide ratio | [6] |
AD | APP (V717I, PSEN1, R278K) | Hippocampal spheroids | Disease modeling | Increased Aβ42/Aβ40 peptide ratio | [7] |
Decreased synaptic protein levels | |||||
Examination of early pathological changes in humans | |||||
AD hippocampal parenchyma-like model | |||||
AD | PSEN1 (A246E) | Cerebral organoid | Disease modeling | AD-like pathology | [8] |
PSEN2 (N141I) | React to β- and g-secretase inhibitors by decreasing levels of Aβ peptide | ||||
Developmental and tissue patterning defects | |||||
Single cell-sequencing revealed altered development and signs of premature differentiation | |||||
AD | APP knockin or knockout | Neuron | Genome-wide molecular profiling | An isogenic APP Swe/PSEN1 M146V ‘‘double-mutant’’ iPSC line (dAP) homozygous for both APP swe and PSEN1 M146V was developed, in addition to other various fAD mutated iPSC lines | [12] |
PSEN knockin | Total of 16 iPSC fAD lines (8 APP mutated lines, PSEN1 mutated lines, and 1 dAP iPSC line) were used. All iPSC lines were edited by CRISPR | ||||
Common alterations in early endosomes mediated by accumulation of β-CTF, not Aβ | |||||
AD | PSEN1 (G384A) | Cortical neuron | Drug screening | A combination of existing drugs (anti-Aβ cocktail, bromocriptine, cromolyn, and topiramate) synergistically improved Aβ phenotypes of AD | [13] |
This anti-Aβ cocktail decreases toxic Aβ levels in neurons derived from patient cells | |||||
CADASIL | NOTCH3 (R153C, C224Y) | BMEC | Disease modeling | Impaired electrical resistance in mural cells and astrocytes | [24] |
Mural cell | Decreased barrier function and disorganized tight junctions in BMECs | ||||
Astrocyte | |||||
CADASIL | NOTCH3 (R182C, R141C, C106R) | Mural cell | Disease modeling | Increased PDGFRβ expression, abnormal structure and distribution of the filamentous actin network, presence of N3ECD/LTBP-1/HtrA1-immunopositive deposits | [25] |
CADASIL | NOTCH3 (R1076C) | VSMC | Disease modeling | Alterations in gene expression within the NOTCH and NF-κB signaling pathways, as well as cytoskeleton disorganization | [26] |
CADASIL | NOTCH3 (R153C, R182C) | Blood vessel organoid | Disease modeling | Induction of mutations by CRISPR/Cas9 base editing | [27] |
Reduced vessel diameter, accumulation of NOTCH3 extracellular domain, degeneration of mural cells, and increased apoptosis and cytoskeletal alterations | |||||
CADASIL | NOTCH3 (R421C) | VSMC | Disease modeling | iPSC-derived VSMC showed NOTCH3 deposition and abnormal actin cytoskeleton structure | [28] |
Blood vessel organoid | Gene expression downregulation of cell adhesion, vessel development in CADASIL blood vessel organoid | ||||
NOTCH3 mutations could be corrected using the dual Adeno associated virus split- adenine based editor max system | |||||
ALSP | CSF1R (V838L) | - | Disease modeling | Generation of iPSCs from ALSP patient fibroblasts | [33] |
ALSP | CSF1R knockout (CSF1R+/-, CSF1R-/-) | - | Disease modeling | CSF1R Knockout by CRISPR/Cas9 based gene editing | [34] |
ALSP | CSF1R (V784M) | Microglia | Disease modeling | Transcriptomic analysis revealed similarities to human primary microglia | [35] |
Decreased CSF1R autophosphorylation | |||||
Impaired migratory ability | |||||
Reduced P2RY12 expression |
iPSC, induced pluripotent stem cell; AD, Alzheimer’s disease; APP, amyloid precursor protein; PSEN1, presenilin-1; Aβ, amyloid-beta; fAD, familial Alzheimer’s disease; PSEN2, presenilin-2; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; β-CTF, β c-terminal fragment; CADASIL, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy; BMEC, brain microvascular endothelial cell; PDGFRβ, platelet-derived growth factor receptor β; N3ECD, Notch3 extracellular domain; LTBP-1, latent-transforming growth factor β-binding protein-1; HtrA1, high temperature requirement A1; VSMC, vascular smooth muscle cell; NF-κB, nuclear factor κB; ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF1R, colony-stimulating factor 1 receptor; P2RY12, purinergic receptor P2Y12