Cell Stem Cell | Fibroblasts have great powers: Simulate Alzheimer's disease and have their own aging characteristics

Written | Editor Chun Xiao | xi Alzheimer's disease (Alzheimer's disease, AD) patients, except for a small number of familial AD, most of them are sporadic AD, and most of them have no clear genetic cause .

One of the most significant characteristics of sporadic AD is that it occurs concentratedly in the elderly; and, with age, the risk of AD increases exponentially [1].

However, what exactly is the mechanism that leads to this age dependence of AD? People don't fully understand it yet.

Age is crucial to the development of AD, but so far there is no effective in vitro model to simulate nerve cell senescence in vitro.

In the past period of time, researchers tried to use iPSC-differentiated neurons from AD patients to simulate the in vitro cell model of aging-induced AD, but they found that iPSC-induced neurons could not characterize aging [2].

In recent years, researchers have discovered that induced neurons (iNs) derived from human fibroblasts can characterize the characteristics of aging [3, 4].

The emergence of iNs model has brought dawn to the pathological changes of AD neurons, especially related research on aging-induced AD.

On April 27, 2021, researchers such as Jerome Mertens and Fred H.
Gage from the Salk Institute for Biological Research in the United States and the University of Innsbruck in Austria published the title Age-dependent instability of mature neuronal fate in induced in Cell Stem Cell.
A research paper on neurons from Alzheimer's patients.
In this paper, the author uses the method of directly transforming fibroblasts from AD patients into iNs to establish a neuron model that can characterize age.

Through comparison, the author found that iNs derived from AD patients exhibited obvious hypo-mature neuron (hypo-mature) characteristics, including the expression of stress, cell cycle, and dedifferentiation markers.

In addition, at the level of epigenetics, these iNs have epigenetic characteristics similar to aging and malignant transformation/cancer.

In contrast, if fibroblasts from AD patients are first induced to form iPSCs, and then iPSCs are used to induce differentiation into neurons (iPSC-iNs), these neurons will completely lose the disease-related transcriptional characteristics that reflect the elderly AD patients.

These results suggest that iNs directly transformed from fibroblasts can better simulate neurons in the aging brain and can be used as an in vitro research model for aging-related AD.

The author took skin biopsy samples from 16 AD patients (13 sporadic AD and 3 familial AD) and 19 gender- and age-matched normal controls, and directly induced these primary fibroblasts to induce neurons iNs (Figure 1).

These iNs neurons do not need to go through the differentiation path from neural precursors to neurons, but directly form aging neurons corresponding to their source (AD patients or normal control population).

Through whole transcriptome sequencing, the authors found that the transcriptome characteristics of iNs derived from AD patients include neuron failure, stress effects, and neuronal re-entry into the cell cycle, etc.
, which well mimic the known pathological features in the brain of AD patients [ 5,6].

Figure 1: The method of iNs derived from fibroblasts in sporadic AD patients and controls.

Further gene enrichment analysis showed that among the iNs derived from AD patients, the functions of significantly down-regulated genes mainly included nervous system development, neuronal action potentials, synaptic transmission, ion transport, and protein mitochondrial localization.

The functions of the significantly up-regulated genes in iNs derived from AD patients mainly cover cell cycle control, stem cell/progenitor cell maintenance, signal transduction pathways, apoptosis and cancer-related pathways.

By comparing with transcriptome data at different stages of neuron differentiation, the authors found that the characteristics of iNs derived from AD patients are similar to those of hypo-mature neurons.

In addition, iNs derived from AD patients also exhibited features such as elevated reactive oxygen species, DNA damage, and elevated aneuploid DNA content, and these changes may trigger the process of neuronal dedifferentiation and cause abnormal submature cell states.

Subsequently, the author used ATAC sequencing to analyze the epigenetic map of iNs and found that iNs derived from AD are different from iNs derived from normal people at the epigenetic level, and their performance is similar to the epigenetic changes caused by malignant transformation and aging.
, Suggesting that the dedifferentiation state of AD neurons is regulated at the epigenetic level.

In contrast, the author tried another route to iNs formation, that is, the primary fibroblasts were induced to dedifferentiate into iPSCs, and then iPSCs were differentiated into induced neurons, that is, iPSC-iNs.

By comparison, the authors found that unlike iNs, iPSC-iNs neurons induced by iPSC lost the disease-related transcriptome characteristics of aging AD patients.

These results indicate that iNs derived from fibroblasts can better reflect and mimic the in vivo characteristics of the aging AD brain.

This study proved that the iNs model has more advantages than the iPSC model when studying the age-related mechanisms of AD, and it completes and complements the previous iPSC-AD model [7].

At the same time, the transcriptome and epigenetic characteristics of iNs can better reflect the different stages of the adult brain in the aging process.

Therefore, iNs is expected to become a model with wide application potential, to realize the in vitro simulation of sporadic AD, and to provide a powerful tool for the study of the age-dependent pathological mechanism of sporadic AD.

However, it should also be noted that fibroblasts have their own skin cell specificities.
These specificities may still be retained in the iNs that they differentiate, which will affect the characteristics and functions of iNs.
We look forward to the emergence of other iPSC differentiation models in the future.
It mimics the in vivo phenotype of AD disease well.

Original link: https://doi.
org/10.
1016/j.
stem.
2021.
04.
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