'Live' brain models used in hunt for Alzheimer's treatment

'Live' brain models used in hunt for Alzheimer's treatment
Fig. 1: Senescence-related changes in human cortical brain organoids. a Representative images of sections of human cortical brain organoids derived from H9-ESCs cultured over 13 weeks in vitro and stained with SA-β-gal. Scale bar = 1000 µm. Dotted box indicates a magnified image. W is week. b Quantification of the percentage of SA-β-gal area normalized to the total area of each individual organoid derived from H9-ESCs. Data are presented as mean ± standard deviation. ****P < 0.0001 via one-way ANOVA. Number of independent experiments = 3. Total number of analyzed organoids = 72. W is week. c Representative images of sections of different ages of human organoids derived from H9-ESCs. Sections were stained with p21 antibody (red) and counterstained with Hoechst 33342 (blue). Scale bar = 65 µm. W is week. White dotted box indicates the magnified image. d Quantification of the percentage of total p21+ cells relative to the total number of cells per organoids derived from H9-ESCs. Data are presented as mean ± standard deviation. **P < 0.001, *P < 0.01 via one-way ANOVA. Number of independent experiments = 3. Total number of analyzed organoids = 63. W is week. e qRT-PCR of p16 and KL at different stages of in vitro culture of human cortical organoids derived from H9-ESCs. All values were normalized to GAPDH levels of their respective samples, and expressed relative to W1 values to obtain the fold change. Data are shown as mean ± standard error mean; Number of independent experiments = 4. Total number of analyzed organoids = 72; ***P < 0.001, ****P < 0.0001 via one-way ANOVA. W is week. f Western blots showing the protein levels of full-length KL and secreted KL in human cortical organoids derived from H9-ESCs cultured over 13 weeks. Actin was used for normalization. Star indicates the specific band of secreted KL, sKL indicates secreted KL. All blots derive from the same experiment and processed in parallel. g Bar graphs show the quantification of KL, as well as secreted KL levels obtained from f. Data are shown as mean ± standard error mean. The number of independent experiments = 4, total number of examined organoids is 72. sKL indicates secreted KL. h Normalized relative expression values of p16 and KL mRNA obtained from published RNA-seq studies. The fold change was calculated by dividing the normalized mRNA value of different weeks over W1. Data are shown as mean ± standard error mean. W is week. i Heatmap represents the expression of RNA-seq data of senescence increased and decreased markers in cortical organoids derived from iPSCs cultured over different time points. Relative expression data were further normalized between 0 (lowest) to 1 (highest) expression value of individual genes across different time points of organoids culture. Normalized expression values were color-coded with red values indicating upregulation and white values indicating downregulation. W is week. Credit: DOI: 10.1038/s41514-021-00070-x

Studying tiny 'live' models of the human brain has helped researchers understand its aging and find a key to potential treatments for Alzheimer's and other neurodegenerative diseases.

University of Queensland scientists have found different cellular mechanisms that can either accelerate or reduce cell deterioration.

Professor Ernst Wolvetang studied organoids, models that closely mimic the human brain, at UQ's Australian Institute for Bioengineering and Nanotechnology.

"We have found that can be used to study the that drive brain aging processes," Professor Wolvetang said.

"This opens the way for testing many molecules that could become potential therapeutic drugs for a host of neurodegenerative diseases."

Using the organoids, Professor Wolvetang and Dr. Julio Aguado found DNA leakage accelerated aging in the rare neurodegenerative disease Ataxia-Telangiectasia (A-T).

In another research project, Professor Wolvetang and Dr. Mohammed Shaker found that increasing levels of the 'anti-aging' protein klotho reduced the deterioration in brain cells associated with age and dementia.

'Anti-aging' protein and Alzheimer's treatment

Dr. Mohammed Shaker used stem cell technology to grow the organoids, with the cellular make-up and architecture of a developing human brain, to study klotho.

Credit: University of Queensland

"We genetically altered klotho levels to study the effects an increase in the protein would have on organoid —and found that it slowed aging processes by 89 percent," Dr. Shaker said.

"Our research clearly demonstrates that this protein has a powerful and direct effect on reducing the effects of aging in the brain.

"If we can find a way to increase klotho in cells, this could be beneficial in halting or slowing Alzheimer's disease."

The team's research has been published in the journal Aging and Mechanisms of Disease.


Explore further

Could a protein called klotho block dementia and aging?

More information: Mohammed R. Shaker et al, Klotho inhibits neuronal senescence in human brain organoids, npj Aging and Mechanisms of Disease (2021). DOI: 10.1038/s41514-021-00070-x
Citation: 'Live' brain models used in hunt for Alzheimer's treatment (2021, November 2) retrieved 18 January 2022 from https://medicalxpress.com/news/2021-11-brain-alzheimer-treatment.html
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