Functional Characterization Of Healthy And Alzheimer's Disease-Related 3D Neurospheres Formed Using Human iPSC-Derived Glutamatergic Neurons, GABAergic Neurons, And Astrocytes

By Krishna Macha, Carole Crittenden, and Oksana Sirenko, Molecular Devices, LLC, and Rebecca Fiene, Scott Schachtele, Coby Carlson, FUJIFILM Cellular Dynamics, Inc.

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The allelic composition of apolipoprotein E (ApoE) in an individual significantly influences their risk of developing Alzheimer's Disease (AD). For instance, individuals with two copies of the E4 allele (ApoE4/4) have an estimated 65% chance of developing AD by age 85, compared to only a 10% chance for those with two wild-type E3 alleles (ApoE3/3). This stark contrast underscores ApoE4 as a major genetic risk factor for AD and highlights its critical role in the disease's pathogenesis.

ApoE functions as a lipid transport protein, and the human isoforms ApoE3 and ApoE4 differ by only a single amino acid at position 112. Despite this minor difference, the exact mechanism by which ApoE4 disrupts intracellular lipid homeostasis remains unclear. However, studies have shown that the ApoE4/4 genotype can alter the lipidomes of astrocytes derived from human induced pluripotent stem cells (iPSCs).

In this application note, we present methods for modeling AD using iPSC-derived neurons that have been genetically engineered to express different combinations of ApoE alleles (E2/2, E3/3, and E4/4). These models provide valuable insights into the molecular and cellular mechanisms underlying AD and offer a platform for testing potential therapeutic interventions.

Access the full application note to learn more.