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▎Edited by WuXi AppTec Content Team 

Alzheimer's disease (AD) is one of the major diseases that affect human health and is also the most common type of dementia. In order to help many AD patients obtain available treatments, scientists are exploring the disease mechanism through many AD-related cell or animal models to find AD weaknesses that can be targeted.

In order to better study the disease mechanism of AD in the laboratory, researchers usually introduce AD-susceptible gene mutations into animals through genetic engineering. This model represents aAutosomal dominant AD (ADAD)But in the real world, about 95% of AD patients areLate-onset AD (LOAD)LOAD is a type of AD that is closely related to age, with patients older than 65 years of age. Aging is a key risk factor for LOAD, so AD is often referred to as "senile dementia." This shows that there is still a gap between the laboratory model and the situation of most AD patients in reality.

Image source: 123RF

Six years ago, Professor Andrew Yoo of Washington University School of Medicine in St. Louis discovered in his study of Huntington's disease thatSkin cells from Huntington's disease patients can be converted into medium spiny neurons by adding some microRNAs (miRNAs) and transcription factors., and they will also show the corresponding characteristics of Huntington's disease, including DNA damage, mitochondrial dysfunction, cell death, etc. The researchers found that by reprogramming the skin cells of patients of different ages, they can reproduce the progression of Huntington's disease. This also makes them wonder, if this method is replicated in AD patients, can they directly observe the changes in neurons in the LOAD group?

In the latest issue of Science magazine, Professor Yoo and his colleagues demonstrated that this approach is equally feasible and that two types of miRNAs, miR-9/9* and miR-124, play a key role in skin reprogramming in AD patients.When expressed in fibroblasts obtained from adult skin, they can cause chromosome reconstruction in the cells, causing the fibroblasts to lose their original characteristics and activating neural cell programming.。

According to their findings, this method can transform 80% of fibroblasts into neurons. In addition, with the assistance of transcription factors such as human neurogenic differentiation protein 2 (NEUROD2) and human myelin transcription factor 1 (MYT1), it can also produce disease-related neuronal subtypes and exhibit age-related neuropathological characteristics.

The transition from skin to neurons is still the first step of the new study. Professor Yoo and his colleagues want to see whether they have the potential to become a model for simulating LOAD. They tried to culture reprogrammed neuronal cells in a thin gel layer in vitro and found that they could not only divide and grow normally,It can also spontaneously assemble into 3D spherical structures, and provides information on the communication and structure of cortical neurons in the brain.

▲Neurons obtained through reprogramming can spontaneously assemble into spheroids(Image source: Reference [2])

In the study, the authors obtained skin cell samples from three groups of people, including LOAD and ADAD patients, as well as healthy people. The ages of the sample providers were similar. As the culture time went on, the authors observed the status of the three types of neuronal spheroids.

First, samples from ADAD patients showed tau protein disorder, in which many toxic tau protein "seeds" were produced. In addition, the deposition of β-amyloid protein (Aβ) was also observed in the spheroids, and most of the Aβ was concentrated on the outer surface of the spheroids.

Similarly, the neuronal spheroids formed by LOAD-derived samples also rapidly accumulated a large amount of Aβ deposits, and also showed pathological characteristics of tau protein. Tau protein with "seed" characteristics could also be detected in the axon region. In addition,Neurons in the LOAD model undergo spontaneous neurodegeneration and death, with spheroid volume gradually shrinking by 50%, axon formation impaired, and connections becoming discontinuousAll of these conditions suggest what changes may have occurred in the brains of LOAD patients. The authors found that spheroids cultured from healthy human samples also showed some Aβ deposition, but the amount was far less than that of AD patient samples, and it did not affect the normal survival of the spheroids.