Modelling mitochondrial dysfunction in Alzheimer’s disease using human induced pluripotent stem cells

Table 1 Advantages and disadvantages of different systems for modelling Alzheimer’s disease[178]

Model system	Advantages	Disadvantages
Animal models	Can be used to model physiological factors such as diet, obesity and hypertension	Findings may not be able to be directly extrapolated to humans
Postmortem tissue	Human-derived	Difficult to obtain; May be of poor quality due to the destructive effects of AD in its later stages
iPSC-based models	Human-derived; More easily obtained than post-mortem tissue	Cannot be used to model physiological or epigenetic factors; Large variation between sAD iPSC lines (may not exhibit phenotype); Neuronal derivatives may be akin to ‘younger’ neurons

AD: Alzheimer’s disease; iPSC: Induced pluripotent stem cells.

Table 2 List of studies that have used induced pluripotent stem cells to model Alzheimer’s disease

Study	Disease	Key findings	Advantages	Disadvantages
Yagi et al[133], 2011	fAD	Relevant expression of APP and secretase subunits in iPSC-derived neurons	Obvious AD phenotype observed	fAD only represents ~ 5% patients
Shi et al[124], 2012a	DS	AD pathology (such as aberrant Aβ production and hyperphosphorylated Tau) developed over months in culture, as opposed to years in vivo	Show tau (advanced) phenotype	Findings may not be able to be extrapolated to AD
Israel et al[17], 2012	fAD, sAD	fAD neurons and one out of two sAD neurons exhibit altered APP expression and Aβ secretion and swollen endosomes	Comparison of fAD and sAD, in essence using fAD lines as positive control	High levels of variation between cell lines
Koch et al[101], 2012	fAD	Key steps in proteolytic APP processing are recapitulated in hES and iPSC-derived neurons	Obvious AD phenotype observed	High levels of variation between cell lines
Maclean et al[146], 2012	DS	Disturbance of multilineage myeloid haematopoiesis in T21 at fetal liver stage	Reproducible phenotype because clear genetic link	Findings may not be able to be extrapolated to AD
Kondo et al[53], 2013	fAD, sAD	Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in fAD and one out of two sAD patients, also observed ROS	Comparison of fAD and sAD, in essence using fAD lines as positive control	High variation between sAD cell lines
Xu et al[66], 2013	Exogenous Aβ	Cell cycle re-entry in iPSC-derived neurons treated with Aβ	Used pharmacological inhibitors to demonstrate rescue of phenotype	May not be physiologically relevant
Weick et al[142], 2013	DS	Compensatory responses to oxidative stress in T21 neurons, also reduced synaptic activity	Reproducible phenotype because clear genetic link	Findings may not be able to be extrapolated to AD
Woodruff et al[139], 2013	fAD	PSEN1 mutations impair γ-secretase activity but do not disrupt γ-secretase-independent functions	Obvious AD phenotype observed	fAD only represents ~5% patients
Hibaoui et al[143], 2014	DS	Abnormal neural differentiation, likely caused by DYRK1A on chromosome 21	Used fetal fibroblasts to generate iPSCs (less acquired mutations)	Findings may not be able to be extrapolated to AD
Muratore et al[16], 2014	fAD	iPSC-derived neurons have increased Aβ42 and Aβ38, along with increased levels of both tau and phosphorylated tau	Obvious AD phenotype observed	fAD only represents ~5% patients
Mahairaki et al[134], 2014	fAD	Increased Aβ42:Aβ40 ratio in fAD iPSC-derived neurons	Obvious AD phenotype observed	fAD only represents ~5% patients
Sproul et al[135], 2014	fAD	Identified 14 genes that are differentially regulates in PSEN1 mutant NPCs relative to controls	Obvious AD phenotype observed	fAD only represents ~5% patients
Duan et al[131], 2014	fAD	iPSC-derived neurons with ApoE3/4 mutations showed typical AD features	Obvious AD phenotype observed	fAD only represents ~5% patients
Liu et al[67], 2014	fAD	Treatment with NSAID reduced Aβ42:Aβ40 ratio	Obvious AD phenotype observed	fAD only represents ~5% patients
Young et al[128], 2015	sAD	Human neurons with SORL1 mutations associated with sAD show a reduced response to BDNF, at the level of both SORL1 expression and APP processing	Many cell lines used (n = 7)	Only one type of sAD mutation examined; unlikely to be able to be extrapolated to a large patient cohort
Hossini et al[130], 2015	sAD	Genes associated with AD expressed in sAD iPSC-derived neurons (including oxidative stress response). Treatment with a γ-secretase inhibitor reduced levels of Tau.	Show AD-like gene expression patterns	Only one patient line used (n = 1)
Chang et al[147], 2015	DS	Tau mislocalisation	Show advanced (tau) phenotype	Findings may not be able to be extrapolated to AD
Murray et al[144], 2015	DS	Slower proliferation of NPCs, increased Aβ production, a decrease in mitochondrial membrane potential and increased no. and abnormal appearance of mitochondria, also increased no. of ds DNA breaks in T21 neurons	Reproducible phenotype because clear genetic link	Findings may not be able to be extrapolated to AD
Moore et al[15], 2015	fAD, DS	APP mutations increase levels of tau and phosphorylated tau whereas PSEN mutations do not	Obvious AD phenotype observed	Tested drugs (β-secretase and ɣ-secretase inhibitors) that have failed clinical trials
Tubsuwan et al[177], 2016	fAD	Description of model	Obvious AD phenotype observed	fAD only represents ~5% patients
Raja et al[108], 2016	fAD	Brain organoids from AD patients exhibit amyloid aggregation, pTau and endosome abnormalities, treatment with β and γ-secretase inhibitors reduced this pathology	Obvious AD phenotype observed	fAD only represents ~5% patients
Li et al[140], 2016	fAD	Characterisation of an iPSC line	Obvious AD phenotype observed	fAD only represents ~5% patients
Lee et al[119], 2016	sAD	Secretase inhibtors decreased Aβ generation but less potency in 3D	High number of sAD lines used (n = 5)	Tested generic drugs (BACE1 and ɣ-secretase inhibitors) that have failed clinical trials
Yang et al[136], 2017	fAD	Premature neuronal differentiation with decreased proliferation and increased apoptosis in AD-NPCs, Wnt-Notch pathway involvement	Obvious AD phenotype observed	fAD only represents ~5% patients
Dashinimaev et al[145], 2017	DS	Increased Aβ secretion and upregulation of APP gene, also increased BACE2, RCAN1, ETS2, TMED10 expression in T21 neural cells compared to controls	Reproducible phenotype because clear genetic link	Findings may not be able to be extrapolated to AD
Jones et al[98], 2017	fAD, sAD	Astrocytes derived from iPSCs from both fAD and sAD patients exhibit a pronounced pathological phenotype	Comparison of fAD and sAD, in essence using fAD lines as positive control	Only one line each fAD and sAD used (n = 1)
Armijo et al[137], 2017	fAD, sAD	fAD neurons have increased susceptibility to Aβ in comparison to sAD (and control) neurons	Comparison of fAD and sAD, in essence using fAD lines as positive control	Only one line each fAD and sAD used (n = 1)
Ochalek et al[107], 2018	fAD, sAD	sAD iPSC-derived neurons reveal elevated tau hyperphosphorylation, increased amyloid levels and GSK3β activation	Show tau (advanced) phenotype	Differentiation protocol requires 10 weeks at least
Birnbaum et al[74], 2018	sAD	sAD iPSC-derived neurons display oxidative stress and increased mitochondrial protein expression which doesn’t correlate with Aβ/tau	Occurs in ~95% of AD cases	Hard to explain why the oxidative stress and increased mitochondrial protein expression don’t correlate with Aβ/tau

AD: Alzheimer’s disease; iPSC: Induced pluripotent stem cells; DS: Down’s syndrome; APP: Amyloid precursor protein; NPC: Neural precursor cells; Aβ: Beta-amyloid.