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Alzheimer’s Disease, genetic risk factors, and 3D models

Three recently published studies of Alzheimer’s Disease (AD) research suggest
-Known and rare genetic risk factors may bring about alterations in biological function to increase predisposition to the disease
-APOE4 expression relates to physiological changes in cholesterol regulation in oligodendrocytes and
-iPSCs derived from control and AD patients with Presenilin1 mutations can be differentiated into neurons and astrocytes and form self-organized 3D structures to recapitulate the early biochemical and pathological disease features of AD.

In the first publication, researchers from the Netherlands analyzed the characteristics of rare damaging variants (Figure 1). They found that two rare genetic variants of ATP8B4 and ABCA1 genes were associated with AD risk. The researchers suggest that these may offer a predictive tool for early-onset AD and uncover alternative genetic mechanisms that might lead to precision therapeutic approaches for AD patients.

Axol-Bioscience-human-iPSC-image-AD-blog-fig-1.jpgw3.webp
Caption of human iPSC derived cell image from Axol Bioscience AD-blog-fig-1.jpg
Figure 1. Reproduced from Holstege, H., Hulsman, M., Charbonnier, C. et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nat Genet (2022). https://doi.org/10.1038/s41588-022-01208-7. Variant features were investigated in a merged mega-sample (n = 31,905) instead of the meta-sample because this allows for increased accuracy for estimations of variant effect sizes for each variant category/age-at-onset bin. a, Carrier frequency according to age at onset. A carrier carries at least one damaging variant in the considered gene. b, ORs according to age at onset. The effect size significantly decreased with age at onset for SORL1, TREM2, ABCA7, ABCA1 and ADAM10. c, ORs according to variant frequency. The rareness of variants in SORL1 was significantly associated with the effect size. d, cMAC by variant frequency: the stacked total number of cases (dark) and controls (light) that carry gene variants with allele frequencies as observed in the mega-sample. The numbers above the bars indicate the number of contributing variants. Whiskers: 95% CI. Genes in black: genes identified to significantly associate with AD in the meta-analysis; gray: genes not significantly associated with AD in the meta-analysis; blue: genes identified by the targeted GWAS analysis, these were not significantly associated with AD in the meta-analysis.

In the second study, researchers established a functional link between APOE4, cholesterol, myelination, and memory using post-mortem human brains from APOE4 carriers compared with noncarriers. The researchers were able to see aberrant amounts of cholesterol accumulated within the cell bodies of oligodendrocytes in post-mortem APOE4 patients’ brains and were able to recreate this in oligodendrocytes derived from engineered human induced pluripotent stem cells (hiPSC) expressing APOE4. When they were co-cultured with neurons, the APOE4 oligodendrocytes failed to myelinate the neurons as well as APOE3-expressing cells did. 

The final study used human iPSC-derived 3D culture co-culture models of astrocytes and mature neurons expressing mature Tau features that mimicked early AD biochemistry and pathology. Interestingly, and in support of the practical benefits 3D culture offer, they first showed how neuronal differentiation is increased in 3D cultures compared to 2D cultures (Figure 2). The team went on to demonstrate that 3D AD cultures displayed increased total Tau and some evidence of greater insoluble Tau as compared to the 3D control cultures at 6 weeks post differentiation, supporting the thought that AD pathology begins many years before the onset of clinical symptoms.

Axol-Bioscience-human-iPSC-image-AD-blog-fig-2.jpgw3.webp
Caption of human iPSC derived cell image from Axol Bioscience AD-blog-fig-2.jpg
Figure 2. Reproduced from Prasannan, P., Siney, E., Chatterjee, S. et al. A 3D-induced pluripotent stem cell-derived human neural culture model to study certain molecular and biochemical aspects of Alzheimer’s disease. In vitro models (2022). https://doi.org/10.1007/s44164-022-00038-5. Neuronal differentiation is increased in 3D cultures compared to 2D cultures: representative confocal images of immunohistochemistry of 2D-HAD2 cultures stained for Nestin (a), GFAP (b), β3-Tubulin ©, and MAP2 (d). Nestin and β3-Tubulin in red, MAP2 and GFAP in green, DAPI in blue, scale bar, 50 µm. Images were taken using 1.3NA × 63 objective glycerol immersion. The proportion of Nestin (e), GFAP (f), β3-Tubulin (g) and MAP2 (h) positive pixels relative to DAPI + pixels in confocal images across cell lines grown in 2D and 3D culture at 6 weeks post differentiation. g and h left and middle graphs, data per cell line; right graphs, all lines combined. n = 3 independent culture wells for each cell line at each time point, with 3 images analyzed per well. Data represented as mean ± SEM, *p < 0.05, ****p < 0.0001

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