Increasing the expression of a gene slows Alzheimer’s progression in mice

According to recent research, enhancing the expression of one gene in cells that help the brain’s neurons, shields neurons in mouse models of Alzheimer’s disease.

Alzheimers Disease

Image Credit: BRO.vector/Shutterstock.com

The study was published in the journal Nature Communications on January 10th, 2022. Increased activity of the gene—Nrf2—slowed down the physical and cognitive decline in the mice, and also decreased the buildup of the sticky protein in their brains. All these factors are vital markers of Alzheimer’s disease in humans.

The study was headed by Jeffrey Johnson, professor at the University of Wisconsin–Madison School of Pharmacy, and his associates at the University of Edinburgh in Scotland.

Scientists had already found Nrf2 as a therapeutic agent for amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. Now, they are searching for ways to enhance the activity of Nrf2 as a prospective therapy for Alzheimer’s—a disease with few good treatments but no cure.

The team from UW–Madison identified that increasing the Nrf2 levels in support cells, known as astrocytes, aided neurons considerably reduce the buildup of two disordered proteins at the heart of Alzheimer’s.

Tau and beta-amyloid proteins form harmful clumps called tangles and plaques, respectively. The accumulation of these proteins pressurizes neurons and prevents their machinery, thereby, resulting in the death of the neuron and cognitive decline.

On physical and memory tests, there was improved performance of mice that over-expressed Nrf2. Genetic signatures of Alzheimer’s in the mouse models were reversed by boosting Nrf2, implying that they had a prevalent normalizing effect that was more than simply addressing the clumps of tau and beta-amyloid.

The extent of the reduction in beta-amyloid and tau and the nearly complete reversal of the genetic changes is very significant,” states Johnson, who helped in identifying Nrf2’s protective role through astrocytes in other neurodegenerative diseases earlier to this research.

Over 2,300 genes change in one part of the brain in the Alzheimer’s model. And almost all 2,300 go back to normal. I was stunned. I never thought we’d get that outcome.”

Jeffrey Johnson, Professor, School of Pharmacy, University of Wisconsin–Madison

Nrf2 manages the expression of several genes that shield against issues such as inflammation or oxidative stress. Although it is stimulated in the later stage of Alzheimer’s, its stimulation may act too late to safeguard the brain from the disease.

To analyze how the continuous activation of Nrf2 in astrocytes can guard the brain, Johnson bred mice in the laboratory. The mice had over-accumulated beta-amyloid around neurons to imitate Alzheimer’s disease, as well as expressed a lot of Nrf2 in astrocytes.

When compared to mice with no boost to Nrf2, the mice with a lot of the gene had around 90% less beta-amyloid present in their brains. Also, they had beta-amyloid plaques in far fewer numbers.

Memory loss is the one symptom of Alzheimer’s that is common in both mice and humans. Compared to mice with no boosted gene, Alzheimer’s model mice overexpressing Nrf2 also performed far better in a standard memory test—almost like non-Alzheimer’s mice. In addition, mice having extra Nrf2 were far better at navigation on a tight-rope-like bar, which is considered a way of measuring their coordination and balance.

Giles Hardingham, Collaborator, University of Edinburgh, and his team performed similar experiments on mice that had a lot of tau protein buildup. The researchers discovered that tau-heavy mice maintained about 25% more neurons while their astrocytes also had boosted Nrf2. In the cortical neurons of their brains, they also accumulated less tau protein.

Nrf2 overexpression had a very similar impact in both the tau and beta-amyloid models. In both cases, it’s very clear that Nrf2 in the astrocytes is modulating the neuropathology.”

Giles Hardingham, University of Edinburgh

The team doubts whether Nrf2 is boosting neurons’ capacity to digest these proteins as a technique to clear them away. The same way how the gene, which is expressed in the supportive astrocytes nearby but not in neurons, executes this step remains ambiguous. Also, Nrf2 seems to offer extra benefits that are still not well understood, for example, the largely reversing disease-associated genetic changes in the brain.

Although Nrf2 is an interesting agent for anti-Alzheimer’s therapies, stimulating genes in the brain using drugs has proven challenging in the past. Johnson says that next-generation treatments, like gene therapy and therapeutic peptides, might be a better method to stimulate the gene.

Diagnosing patients much earlier is another important factor in developing potential treatments for Alzheimer’s. Researchers have found that Alzheimer’s takes several years, even decades, to fully evolve. Outcomes may be improved by treating Alzheimer’s patients at the earliest possible stages.

New diagnostic tools currently under development will be very helpful.”

Jeffrey Johnson, Professor, School of Pharmacy, University of Wisconsin–Madison

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