Exploring the involvement of oligodendrocytes in Alzheimer’s disease using human iPSCs

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a chronic neurodegenerative disease, characterized clinically by cognitive and neuropsychiatric impairments, and pathologically by extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuroinflammation which ultimately leads to neurodegeneration and dementia. Despite extensive research, no effective treatments have been identified to date, and many clinical trials have failed. This is due, in part, to a lack of human‐specific models for evaluating the contribution of non‐neuronal cell types to the disease pathogenesis; an issue we aim to address with our research into the pathogenic contributions of oligodendrocytes to AD.MethodTo investigate the role of OLs in AD, we are analyzing post‐mortem human brain tissue of AD and appropriate control samples to assess OL distribution between cortical areas with different disease burdens within the same patient using transcriptomic and immunohistochemical approaches. To complement our observations in the human brain, we are using human iPSC‐derived oligodendrocyte model systems in 2D and 3D to study how AD‐associated mutations, as well as exposure to AD‐related environmental stress may impact OL physiology.ResultThus far, our analysis of post‐mortem human brain tissue has revealed region and layer‐specific loss of oligodendrocytes in AD. With our in‐vitro models, we have seen morphological differences between human iPSC‐derived OLs carrying AD‐related mutations and isogenic wild‐type controls. We study OL/neuronal interactions in our in‐vitro model systems, as well as in‐vivo via transplantation of iPSC‐derived OL‐precursors into myelin‐deficient mice to allow visualization of their myelination capacity.ConclusionOligodendrocytes (OLs) are known primarily as the myelinating cells of the central nervous system, but have other important functions as well, including providing trophic support to neurons. Accumulating evidence suggests that OLs play an active pathogenic role in AD ‐ historically considered a neuronal disease ‐ but this role has not yet been investigated. The methods we are implementing will help us to identify OL‐mediated mechanisms which may contribute to the pathogenesis and progression of AD, to shed new light on a prevalent neurodegenerative disorder, and to identify novel therapeutic approaches in the future.