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.
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.