- A new study shows that inhaling menthol improves cognitive function in animal models of Alzheimer’s disease.
- Researchers found that menthol inhalation decreased the level of interleukin-1-beta, a protein that causes inflammation.
- Lower IL-1-beta levels were linked to better cognitive function in healthy mice and mice with Alzheimer’s.
- The findings suggest the possibility for some inhaled substances to help treat Alzheimer’s disease.
According to a recent study in mouse models, published in Frontiers in Immunology, repetitive brief exposure to methanol can impact the immune system and prevent the cognitive decline that occurs among individuals with Alzheimer’s disease.
Researchers found that when mice smelled this substance, the level of interleukin-1-beta decreased. This protein is associated with the inflammatory response.
Additionally, by blocking this protein with a drug used to treat autoimmune conditions, researchers were able to boost cognitive ability in the mice with Alzheimer’s-like symptoms.
These findings illustrate the ability of odors and immune modulators to potentially treat this neurodegenerative disease.
“The study is interesting in that it brings to light the fact that, through the olfactory (smell) pathways, we can modulate the brain,” Dr. Brett Osborn, a board-certified neurosurgeon, chief of neurosurgery at St. Mary’s Medical Center in West Palm Beach, FL, not involved in this research, told Medical News Today. “We can effect a positive change on the brain through smell and smell alone.”
Furthermore, this does not require the implantation of a deep brain stimulator electrode or a vagal nerve stimulator system. The study demonstrates that the rodent Alzheimer’s brain can not only be “accessed” but positively affected at the cellular level — in the form of a disease-modifying therapy — through the nasal passages, Dr. Obsorn added.
“The findings that smelling menthol is sufficient to mitigate genetic predisposition to Alzheimer’s disease progression to cognitive dysfunction are provocative,” said Dr. Mikhail Kolonin, professor and director of the Center for Metabolic and Degenerative Diseases with the Institute of Molecular Medicine at UTHealth Houston, TX, who was not involved with this study. “Loss of smell has been previously linked to cognitive impairment and biomarkers of Alzheimer’s disease in patients.”
The study identifies the clear role of regulatory T cells (T-regs), immune cells with immunosuppressive activity, in mediating cognitive function in mice modeled to develop Alzheimer’s disease.
This is an important finding, which currently does not have a mechanistic explanation, Dr. Kolonin noted.
“It is striking that menthol inhalation and T-reg blockade had comparable potency in mitigating cognitive impairment,” said Dr. Kolonin. He explained:
“Because [the] authors conclude that T-reg blockade and olfaction appear to be mediated by the same cytokines, the details of their signaling could explain the underlying mechanisms. It is known that under proinflammatory conditions T-regs produce IL-17, a cytokine that triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. It is surprising that IL-17 was not pursued in the study as a potential mechanistic link.”
Menthol lowers inflammation in the part of the brain associated with memory.
“There appears to be an immunomodulatory effect of menthol in the prefrontal cortex, an area related to memory input, and one that is dysfunctional in the Alzheimer’s patient,” explained Dr. Osborn.
“More specifically, menthol inhalation reduced the cytokine (inflammatory chemicals) load in this region in the rodent Alzheimer’s model relative to the control group. The result? A less inflamed brain,“ he added.
“This effect is theorized to be at least one of the mechanisms by which the [Alzheimer’s disease] mice in the menthol-exposed group exhibited improved cognitive function,“ Dr. Osborn continued.
Inflammation and Alzheimer’s are closely intertwined, and therapies such as menthol inhalation may be beneficial in treating this disease.
“The study reinforces the fact that Alzheimer’s disease is underpinned by inflammation and that if therapies can be engineered to address this pathogenic component, the onset of [Alzheimer’s] may be delayed, and its progression thwarted,” Dr. Osborn stated.
“Potentially, this therapy could be administered via an inhaled agent, menthol, for example, that would be directly delivered to the limbic system of the brain — responsible for our emotions and memory — via the olfactory nerves, as there are neuronal connections between the olfactory and limbic systems,” he pointed out.
“There is a direct connection between the olfactory nerves/ tracts and the limbic system,” said Dr. Osborn. “The limbic system is associated with memory processing, emotional responses, fight-or-flight responses, aggression, and sexual response.”
It is also important to note the connectivity of the limbic system to the olfactory system is responsible for the intimate association of memory and smell.
While emphasizing that the study did not employ aromatherapy, “[o]dors often stimulate memory,” Dr. Osborn further explained. “They also may conjure up emotions, good or bad. In the context of the latter, this may confer a survival benefit: A toxic odor may cause us to run away or flee for fear of a chemical/ toxin exposure, as the flight-or-flight centers are activated by the smell alone.”
Since this study was only conducted on animals, there is no way of knowing how a human would be affected.
“This is a rodent model,” said Dr. Osborn. “It is often the case that such studies do not map to a human. There are a variety of interspecies genetic, anatomic, metabolic and physiologic differences that account for this phenomenon.”
In addition, only menthol was tested as an olfactory stimulant in the study.
“It was not assessed if the effect is specific for cold-sensing neuron activation and the likely role of TRPM8 signaling was not addressed,” Dr. Kolonin cautioned. “It would be interesting to determine if heat sensing stimulation would have similar or opposite effects.”
Another limitation of this study is that immune cells implicated in the process along with T-regs were not characterized.
“It is not clear what T-cells are reduced by menthol in the brain and determining whether those are effector, killer, or other T-cells would be insightful,” said Dr. Kolonin. “Brain microglia and astrocytes, the cells likely responsible for the secretion of IL-1-beta and IL-6, the cytokines modulated by menthol and T-regs, have also not been analyzed.”
“While the authors conclude that inhibition of T-regs reduced both IL-1-beta and IL-6, their data consistently show that IL-6 expression is in fact upregulated.
IL-6 is a cytokine that can play distinct context-dependent and time-dependent roles. It would be interesting to determine if/ how intermittent/ transient modulation of IL-6 may be beneficial for disease intervention.”– Dr. Mikhail Kolonin
“In this study, cognitive function tests were limited to measuring mouse freezing upon fear conditioning,” continued Dr. Kolonin.
“However, this test has a stress behavior component, which complicates data interpretation. It would be advantageous to use water maze or novel object recognition tests, better fit for Alzheimer’s symptoms assessment,” he added.
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