Summary: Brain organoids can be used to study molecular mechanisms that drive brain aging and neurodegenerative disorders. The mini-brains allow for the testing of molecules that could become potential therapeutic treatment options for neurodegenerative diseases.
Source: University of Queensland
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 brain 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 human brain organoids can be used to study the molecular mechanisms 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.
“We genetically altered klotho levels to study the effects an increase in the protein would have on organoid brain cells—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 human brain cells, this could be beneficial in halting or slowing Alzheimer’s disease.”
Klotho inhibits neuronal senescence in human brain organoids
Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear.
Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively.
We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence.
In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.