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New iPSC-model of Alzheimer's Disease Points to Viable Therapeutic Approaches



Review of “Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector” from Nature Medicine by Stuart P. Atkinson

The lack of adequate human model systems currently impedes the development of effective treatments for Alzheimer's disease (AD); however, generating and differentiating patient- and disease-specific induced pluripotent stem cells (iPSCs) may provide an exciting means to study disease pathogenesis in relevant cell types. 

Now, researchers from the laboratory of Yadong Huang (Gladstone Institute of Neurological Disease/University of California, San Francisco, CA, USA) have assessed the potential of neurons derived from iPSCs expressing the Apolipoprotein E4 (ApoE4) APOE variant as a new AD model system. ApoE4 represents a major genetic AD risk factor [1, 2] and ApoE4 expression promotes the formation of the intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques typical of AD [3]. Excitingly, the new study from the Huang laboratory, published in Nature Medicine, now employs this iPSC-based model system to develop a potentially exciting therapeutic approach for ApoE4-related AD [4].

Wang et al. discovered that neurons derived from ApoE4-expressing iPSCs exhibited high levels of APOE fragmentation, tau phosphorylation (independent of amyloid-β peptide levels), amyloid-β peptides, and GABAergic neuron degeneration and death. Of note, ApoE4 expression failed to promote pathological features in mouse neurons, suggesting species-specific effects and providing a potential reason behind the failure of treatment approaches developed in animal models. 

The authors hypothesized that the presence of ApoE4 in neurons led to the gain of toxic effects (rather than a loss of normal function) and in support of this hypothesis, the reintroduction of ApoE4 into the APOE-null human neurons prompted the appearance of the previously noted pathological features. 

Interestingly, both the conversion of ApoE4 to ApoE3 by zinc-finger nuclease (ZFN)-mediated gene editing in iPSCs and the conversion of an ApoE4 function to an ApoE3-like function via the application of small-molecule structure corrector (PH002) to affected neurons rescued disease phenotypes. Patients expressing ApoE3 display a significantly lower lifetime risk estimate of developing AD [5], and so structure corrector treatment may represent an exciting therapeutic approach for ApoE4 AD.

For more on iPSC models of AD and the development of potentially exciting new treatment approaches, stay tuned to the Stem Cells Portal!


  1. Corder EH, Saunders AM, Strittmatter WJ, et al., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-3.
  2. Saunders AM, Strittmatter WJ, Schmechel D, et al., Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993;43:1467-72.
  3. Huang Y and Mucke L, Alzheimer mechanisms and therapeutic strategies. Cell 2012;148:1204-22.
  4. Poppe D, Doerr J, Schneider M, et al., Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine‐Releasing Capacity. STEM CELLS Translational Medicine 2018;7:477-486.
  5. Genin E, Hannequin D, Wallon D, et al., APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 2011;16:903-7.