Three-dimensional cell culture technologies in the study of Alzheimer’s disease: a narrative review

Alzheimer’s disease has become a global public health priority, and there is currently no cure. It is characterized by memory loss and cognitive decline, with typical manifestations including amyloid plaques and neurofibrillary tangles. Unfortunately, these features often fail to replicate in conventional models. The emergence of brain organoids, three-dimensional cultures derived from induced pluripotent stem cells, provides a revolutionary approach to studying Alzheimer’s disease. Brain organoid technology is an emerging 3D cell culture method that can mimic the cellular composition and structure of the human brain. Induced pluripotent stem cells from patients can be used to create brain organoids that preserve the patient’s genetic and epigenetic traits, opening up the possibility of personalized medicine. This allows researchers to explore how genetic factors influence the pathogenesis of Alzheimer’s disease while providing an unprecedented platform for modeling the disease and exploring therapeutic exploration. Herein, we aim to highlight the potential of brain organoids in advancing Alzheimer’s disease research. Compared to traditional animal models, brain organoids offer a more accurate and ethical platform for studying Alzheimer’s disease and testing treatments. Brain organoids are generated from induced pluripotent stem cells that are reprogrammed from the patient’s somatic cells. They can differentiate into various nerve cell types, including neurons and glial cells, while retaining the patient’s genetic and epigenetic characteristics. This capability enables personalized disease modeling and drug screening. The review explores methods for generating brain organoids and discusses the direct reprogramming of somatic cells into induced neural progenitor cells and induced neurons, which can autonomously differentiate into complex brain-like structures. Despite thier potential for therapeutic applications in Alzheimer’s disease, brain organoids face challenges, including a lack of proper vascularisation and maturation. The lack of a functional blood-brain barrier in brain organoids limits their ability to mimic neurovascular interactions and the permeability of therapeutic drug. Furthermore, current strategies primarily focus on generating excitatory neurons, while the generation of interneuron phenotypes remains more challenging, posing a significant limitation for modeling complex brain circuits. Innovative solutions have been proposed to address these challenges, such as the use of rotating bioreactors to enhance oxygen and nutrient supply, as well as the integration of gene editing techniques such as CRISPR-Cas9 to correct gene mutations or enhance protective genes within organoids. In this review, we also discuss the potential of bioprinting to create defined neural pathways in organisms. This pioneering approach could revolutionize the modeling and study of neural connections in Alzheimer’s disease. In summary, the review provides an overview of current technologies and future directions for brain organoids, emphasizing the transformative impact of these technologies in Alzheimer’s disease research. This work plays a crucial role in unraveling the complexity of the disease and facilitating the development of targeted therapies.