Exercise-Induced Hormone Irisin May Help Combat Alzheimer's Disease

A new study in the journal Neuron suggests irisin, a hormone produced during exercise, has potential as an Alzheimer's treatment. Researchers found irisin reduces Aβ, a protein that builds up in Alzheimer's brains, by boosting levels of an enzyme called neprilysin that breaks down Aβ. Irisin also calmed overactive cells and reduced abnormal neuron processes linked to the disease. The study suggests irisin works by interacting with receptors on astrocytes, brain cells that help clear waste. This is a promising discovery, but more research is needed to determine the best way to use irisin for Alzheimer's treatment.

Key Findings

1. Irisin, an exercise-induced hormone, reduces Aβ pathology in a 3D model of AD. This suggests irisin may be a target for treating AD.

2. Irisin works by increasing the levels of neprilysin (NEP), an enzyme that degrades Aβ, secreted by astrocytes. This helps clear Aβ from the brain.

3. Irisin reduces the downregulation of ERK-STAT3 signaling pathways, which are involved in astrocyte activation. This suggests irisin may have anti-inflammatory effects in AD.

4. Irisin treatment reduces dystrophic neurites, and abnormal neuronal processes associated with AD, and lowers the hyperexcitability of cells. This may contribute to improved cognitive function.

5. Integrin αV/β5 on astrocytes acts as the receptor for irisin. This is essential for irisin's effects on NEP secretion and Aβ reduction.

6. These findings suggest exercise-induced irisin may play a role in reducing Aβ burden. This opens doors for developing new therapeutic approaches for AD.

Irisin: A Potential Therapeutic Target to Reduce Aβ Burden for Alzheimer's Disease Treatment and Prevention

Alzheimer's disease (AD), the most common form of age-related dementia, is characterized by progressive memory loss and severe cognitive impairment. A pathological hallmark of AD is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in animal models of AD, but the underlying mechanisms have remained unclear. This article explores the potential of irisin, an exercise-induced hormone, as a therapeutic target for AD by reducing Aβ burden. It summarizes a recent study that investigated the cellular and molecular mechanisms by which irisin attenuates Aβ pathology.

Irisin and Aβ Pathology

Irisin is a myokine, a hormone secreted by muscles in response to exercise. It regulates glucose and lipid metabolism and increases energy expenditure. Interestingly, irisin is also present in human and mouse brains, and its levels are reduced in patients with AD and in mouse models of the condition. Studies have shown that exercise increases circulating irisin levels in humans.

New Study on Irisin and Aβ Pathology

Researchers used a 3D human neural cell culture model of AD to investigate whether irisin affects Aβ pathology. They found that irisin significantly reduced Aβ levels by:

• Increasing the levels of soluble neprilysin (NEP) secreted from astrocytes. NEP is an enzyme that degrades Aβ.

• Downregulating ERK-STAT3 signaling pathways, which are involved in astrogliosis (activation of astrocytes).

Key Findings of the Study

The study identified several key findings regarding irisin and its impact on Aβ pathology:

• Irisin treatment reduced Aβ40 and Aβ42 levels in the conditioned media and 3D gel matrix of the cell cultures.

• Irisin did not cause cell death and did not affect APP processing, suggesting it reduces Aβ levels through other mechanisms.

• Irisin treatment significantly reduced dystrophic neurites, which are abnormal neuronal processes associated with AD pathology.

• Irisin treatment also reduced the hyperexcitability of cells in the 3D-AD cultures.

• Irisin increased the levels of secreted NEP, the enzyme responsible for Aβ degradation.

• Irisin's ability to increase NEP activity and reduce Aβ levels was mediated by ERK-STAT3 signaling.

• Integrin αV/β5 on astrocytes acted as the irisin receptor, essential for irisin's effects on NEP secretion and Aβ reduction.

Implications for AD Treatment and Prevention

These findings suggest that irisin plays a crucial role in the exercise-induced reduction of Aβ burden. By increasing NEP activity and reducing astrocyte reactivity, irisin offers a promising target for developing therapeutic strategies for AD treatment and prevention.

To Summarise

Researchers used a 3D model mimicking the human brain with Alzheimer's. They treated these mini-brains with irisin and found surprising results:

• Aβ Buster: Irisin significantly reduced Aβ levels, working like a cleaner, removing the harmful clumps.

• NEP Hero: Irisin achieved this by increasing an enzyme called neprilysin (NEP) produced by astrocytes (brain cleaning cells). NEP acts like tiny scissors, chopping Aβ into smaller pieces for easier removal.

• Calming Effect: Irisin also calmed down overactive cells and reduced abnormal neuron processes, both linked to Alzheimer's.

• Unlocking the Door: The study discovered that irisin interacts with specific receptors on astrocytes, like a key fitting into a lock, to trigger these beneficial effects.

Hope for the Future:

These findings are exciting because they suggest irisin, boosted by exercise, might help combat Alzheimer's. However, more research is needed:

• Timing and Dosage: Scientists need to figure out the best timing and amount of irisin for maximum benefit.

• Brain Regions: Different brain areas might respond differently to irisin.

• Beyond Astrocytes: Are there other receptors for irisin that contribute to its effects?

• Microglia Matters: Microglia are other brain immune cells. Do they play a role in irisin's actions?

Overall, this study sheds light on a promising new target for Alzheimer's treatment. Irisin's ability to reduce Aβ and calm brain activity warrants further investigation to develop effective strategies for preventing and treating this debilitating disease..

Reference

Kim, E., Kim, H., Jedrychowski, M. P., Bakiasi, G., Park, J., Kruskop, J., Choi, Y., Kwak, S. S., Quinti, L., Kim, D. Y., Wrann, C. D., Spiegelman, B. M., Tanzi, R. E., & Choi, S. H. (2023, November). Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron, 111(22), 3619-3633.e8. https://doi.org/10.1016/j.neuron.2023.08.012

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