The correlation between smoking and neurodegeneration is well established, with one 2011 study finding that heavy smoking in midlife was associated with a more than 100% increased risk of dementia, Alzheimer’s disease, and vascular dementia more than 20 years later.
Dementia is an understudied effect of smoking, and the reason is simple and frightening. It develops later in life, and smokers tend to die younger.
Many of the theories about smoking and dementia revolve around the effects of smoking on the vascular and respiratory systems, essentially blocking the flow of oxygen to the brain after decades of continuous smoking. But a new study from the University of Chicago was released today. scientific progress This suggests that nicotine-induced miscommunication between the lungs and brain may be involved.
Their research uncovered a previously unmapped pathway from the lungs to the mind through pulmonary neuroendocrine cells (PNECs). When exposed to nicotine, these cells release exosomes that disrupt the iron balance of neurons, causing symptoms common in dementia patients.
“This study establishes a clear ‘lung-to-brain’ axis that helps explain why smoking is associated with cognitive decline and neurodegenerative risk,” said University of Chicago postdoctoral fellow Quy Zhang, co-lead author of the new study. “Understanding how these exosomes disrupt iron homeostasis opens new doors for protecting neurons from smoke-induced damage.”
Whether or not this proves to be a causal link to dementia, the study itself is a powerful advance in scientists’ understanding of the lungs.
“We now show that the lungs are not just passive targets of smoke exposure, but active signaling organs that influence brain pathology,” said corresponding author Ast. Professor Joyce Chen of the University of Chicago Pritzker School of Molecular Engineering (PME) and the Ben May Cancer Research Division;
From lungs to brain
PNECs are unique lung cells that combine the functions of both neurons and endocrine cells. Synapses and hormones speak both languages and are important sensors in the airways, but they are difficult to study.
“The main challenge was the extreme rarity of PNECs, which make up less than 1% of lung cells, making it nearly impossible to isolate and study them in detail,” Zhang said.
To study these elusive and important cells, the research team generated large numbers of induced PNECs (iPNECs) that could be studied in the lab by differentiating human pluripotent stem cells.
When exposed to nicotine, iPNECs released large amounts of exosomes, which are small particles containing biological materials such as proteins, lipids, and nucleic acids. Most cell types produce exosomes, but the specific exosomes produced by iPNEC in response to nicotine were rich in a protein called serotransferrin, which the body uses to regulate the flow of iron through the bloodstream.
Applying this model to the human body could mean that every time you take a puff from a cigarette, cigar or e-cig, your lungs’ natural PNEC releases a large amount of the substance, which affects how your body processes iron.
“This nicotine affects PNECs, and these PNECs end up releasing a large amount of exosomes, which causes a disruption in terms of iron homeostasis,” said co-first author Abhimanyu Thakur. During his research, he was affiliated with the PME and Ben May Departments at the University of Chicago, and is currently employed in the Department of Neurosurgery at Harvard Medical School. “We are discovering neurodegeneration-related markers that are elevated and may be associated with many cognitive and dementia-related diseases.”
Work with an eye to the future
This massive release of serotransferrin is essentially misdirecting the body to change the way it regulates iron. The vagus nerve snakes its way from the brain to organs throughout the body, regulating involuntary movements such as heartbeat, breathing, and digestion, and is thought to send messages back to the brain.
“This abnormal iron homeostasis causes oxidative stress, mitochondrial dysfunction, and increased alpha-synuclein expression, which are hallmarks of neurodegenerative diseases,” Chen said.
When a neuron’s iron balance is disrupted, it can inadvertently trigger ferroptosis, a type of programmed cell death, in cells that weren’t supposed to die. Previous studies have linked ferroptosis to both Alzheimer’s disease and Parkinson’s disease, but more research is needed to claim a causal relationship.
The researchers are next looking at whether blocking the original source of the signals, exosomes, could have therapeutic applications. Although direct impact on humans is still years away, this research has deepened scientists’ understanding of how the brain and lungs communicate.
“Understanding communication pathways across these organs is important for developing better prevention and intervention strategies for neurodegenerative diseases,” Chen said.
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DOI: 10.1126/sciadv.ady2696
