Researchers probe impact of pollution on the brain

BY JASMIN FOX-SKELLY

Air pollution isn’t just affecting our respiratory health and curtailing life expectancy, it’s also making our brains sick – and may be a trigger for Alzheimer’s, Parkinson’s, bipolar disorder and even depression, reports Jasmin Fox-Skelly

In the early 2000s, paediatrician Lilian Calderón-Garcidueñas became concerned about the health impacts of air pollution in Mexico City. A few years earlier, the UN had declared the metropolis to be the most polluted city on Earth. Heavy traffic coupled with the city’s high altitude had created a toxic mix brimming with lead, carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone and particulate matter (PM). At the time, the link between these gases and respiratory conditions such as pneumonia, bronchitis and asthma was well known. But Calderón-Garcidueñas was more interested in the impacts on the brain.

Calderón-Garcidueñas did a study where she looked at the brains of children and young adults who died prematurely from car accidents or gun violence in Mexico City. Her research showed that Mexico City residents had clumps of a misfolded protein called amyloid beta in their brain – the classic hallmark pathology of Alzheimer’s disease ^[1].

A later study by Calderón-Garcidueñas showed that out of 203 brains taken from deceased Mexico City residents, 202 had amyloid beta plaques. The plaques were even present in the brain of an 11-month-old baby ^[2]. Meanwhile, stray dogs living in Mexico City had the same plaques in their brains too ^[3].

‘In many cases, the pathology began in the lining of the nose, suggesting that early childhood exposure as young as 11 months of age may be planting the seeds for future cases of Alzheimer’s disease,’ says Ray Dorsey, Professor of neurology at the University of Rochester, US.

Alzheimer’s is a progressive neurodegenerative condition characterised by memory loss, confusion and cognitive decline. Over the past few decades researchers have documented an alarming uptick in cases. The number of people diagnosed with dementia topped 57m in 2019, and experts predict that by 2050 this will rise to 152.8m ^[4]. It isn’t the only neurological disease that’s seen an astonishing jump in cases. Parkinson’s disease is the fastest growing neurological disorder worldwide, with cases doubling between 1990 and 2015 ^[5]. Meanwhile, deaths from motor neuron diseases increased 12.4% from 1990 to 2019.

Increasingly, scientists are blaming air pollution. Research shows people exposed to high levels of air pollution in childhood are more likely to suffer neurological conditions later in life. In the US, for instance, the rate of cognitive decline of women in their 70s increases in more polluted areas, while improvements in air quality led to slower rates of decline ^[6]. A 2023 study, meanwhile, showed that people breathing in ‘average’ levels of air pollution in the US have a 56% greater risk of developing Parkinson’s compared with those living in regions with the lowest level of air pollution ^[7]. A 2023 meta-analysis linked exposure to air pollution during childhood and adolescence to depression and suicidal behaviour ^[8].

‘It’s not a matter of “if” anymore. We know that air pollution causes neurological disease, it’s not even up for discussion,’ says Amedeo D’Angiulli, a neuroscientist at Carleton University in Ottawa, Canada. ‘What we are discussing now are the details; what compounds cause what conditions, and how?’

Pinpointing the exact culprit is easier said than done. Pollutants in air include sulfur dioxide (SO2), lead (Pb), ozone (O3), nitrogen oxides (NOx), and carbon monoxide (CO). Recently, attention has turned to particles less than 2.5µm in diameter, so-called PM2.5 particulates. These particles are small enough to cross the blood-brain barrier (BBB), the protective membrane encasing the brain that filters out most toxins. Researchers at the University of Southern California, US, scanned the brains of over 9000 children aged between nine and 19 and found that those exposed to higher levels of PM2.5 showed differences in the neural architecture of their brains, including what the researchers described as ‘altered patterns of cortical thickness and differences in the microstructure of grey and white matter’ ^[9].

‘What we see is the connectivity between the grey areas in the cortical and subcortical areas is reduced,’ says D’Angiulli. ‘If the tissue is less densely packed it means the connections are less efficient.’

That could explain the reduced cognitive abilities of children growing up in heavily polluted cities. In the early 2000s, D’Angiulli teamed up with Calderón-Garcidueñas and found that children living in Mexico City showed substantially poorer cognitive skills, compared with children of a similar age living in less polluted areas. They were able to pinpoint the cognitive deficits to key developing areas of the brain, including the prefrontal, temporal and parietal lobes of the cortex ^[10].

‘We found direct evidence of early accelerated neurodegeneration in children,’ says D’Angiulli. ‘Not only do they perform poorly in cognitive tests, but about 25% of children that we have seen in Mexico City have amyloid plaques like you see in Alzheimer’s disease.’

How exactly pollutants cause Alzheimer’s disease is unknown. One theory is that inhaled pollutants travel up to and weaken the BBB, allowing more and more toxins to cross into the brain’s blood supply. Once there, the toxins are flagged as an enemy by microglia – the brain’s resident immune cells, which are constantly patrolling looking for pathogens.

‘When these particles get into the brain, the body tries to defend itself to counteract what it sees as an infection,’ says D’Angiulli.

Over time, however, constant activation changes the microglia – causing them to go rogue and release inflammatory molecules called cytokines and reactive oxygen species (ROS). In other words, they start attacking the body’s own neurons and the connections between them.

It’s possible that, at least initially, amyloid plaques are produced by neurons as a kind of defence against this destruction. Post-mortem brain scans show the amyloid plaques are often located physically close to dark spots of particulate matter.

‘There is a theory that plaques are basically a protective mechanism to contain the destructive effects of the particles,’ says D’Angiulli. ‘They act like a scar, patching up damaged tissue. Initially they appear to prevent further neural tissue from dying. But over time the scars disrupt the connections within the white matter, leaving holes everywhere.’

Air pollutants may not even have to enter the brain to damage neurons. Chronic irritation of the airway by pollutants can induce a systemic inflammatory response, which makes the BBB leaky, allowing pro-inflammatory cytokines to rush into the brain and cause neural inflammation and injury. Michael Caudle, Professor of environmental health at Emory University, US, believes that lipopolysaccharides – a component of Gram-negative bacterial cell walls that can often attach to and be associated with PM2.5 particles – may be behind the loss of dopamine neurons in the substantia nigra. In a healthy person, dopamine-producing neurons in the substantia nigra project to and communicate with neurons of the basal ganglia. This connection is vital for the fine control of movement and coordination. However, in Parkinson’s disease the neurons in the substantia nigra die, causing the classic tremors associated with the condition. What causes the neurons to die is up for debate. Caudle believes lipopolysaccharides could cause systemic inflammation, weakening the BBB and leading to neural injury.

However, Dorsey has a different idea. In a recent study, he argues that when toxic chemicals found in air pollution are inhaled, they can enter the brain via the nerve responsible for smell ^[11]. Once there, the toxins damage neurons in the olfactory bulb, which sits right behind the nose. ‘Most air pollution is coughed or sneezed out, but some of it – so called particulate matter – is 1/30th the width of our hair. Some may be small enough to pass through a human neuron,’ says Dorsey. ‘I think the nose is the front door of the brain and these chemicals are exploiting that.’

According to Dorsey, it’s possible that toxic metals such as lead from gasoline, or platinum from catalytic converters, could hitchhike on the little pieces of dirt contained within particulate pollution. These toxic metals could then cause a protein found in neurons, called alpha-synuclein, to misfold, possibly by interfering with the electrostatic interactions within the protein that help it maintain its precise 3D structure.

‘The protein misfolds and clumps together in Lewy bodies, which are like cellular garbage bags. This misfolded protein can stress nerve cells and damage them,’ says Dorsey.

There’s evidence to support this theory. For example, one of the first symptoms of both Parkinson’s and Alzheimer’s disease is a loss of smell. In addition, when you look under the microscope at the brains of people who have died of Parkinson’s disease, the neurons in the substantia nigra are packed full of Lewy bodies, the cellular garbage bags full of misfolded alpha-synuclein. It’s possible, therefore, that misfolded alpha-synuclein proteins can spread from nerve cell to nerve cell, travelling up into the brain.

‘It’s like dominoes falling, one after another,’ says Dorsey. ‘If you have a misfolded protein that begins in the smell centre, it can then spread through the amygdala – a connecting station like in an airport – and then it can go back to the substantia nigra.’

So, given what we know, are there measures that we can take to improve the health of our brain and protect ourselves from neurological disorders? The first step is to improve the quality of the air we breathe, especially in urban areas. Moving away from combustion engines to electric vehicles will help, as will better planning of urban areas and speed restriction zones. There is also evidence that eating foods high in antioxidants may help reduce some of the harmful effects of pollution.

In his review article, Dorsey points to studies suggesting that curcumin, a compound found in turmeric, can mitigate some of the neurological damage caused by air pollution, reducing oxidative stress and inflammation and improving cognitive function. Resveratrol, present in grapes and other fruits, also possesses antioxidant and anti-inflammatory properties. Studies suggest it too could improve cognitive function by reducing oxidative stress and inflammation caused by air pollution. Meanwhile, research has shown that omega-3 fatty acid supplements can also decrease oxidative stress and inflammation in the brain, enhancing cognitive function.

However, these measures are not a substitute for actions aimed at reducing air pollution, experts contend. ‘We’re spending a lot of time trying to cure preventable diseases,’ says Dorsey. ‘Many of these diseases are fundamentally preventable, and if we cleaned our air, food and water, we would reduce the number of individuals developing Parkinson’s disease, Alzheimer’s disease and ALS (amyotrophic lateral sclerosis).’

Pollution trigger for cancer

Charles Swanton, Professor of cancer biology at the Francis Crick Institute in London, UK, is leading a clinical study called TRACERx, which is analysing in unprecedented detail how lung cancers change at the genetic level over time. He has discovered that when a person experiences chronic inflammation, for example, by being exposed to air pollution, the body’s own immune cells can initiate the process of cancer development. Specifically, chronic exposure causes two immune cell types – monocytes and macrophages – to release an inflammatory cytokine called interleukin-1β. That in turn causes premalignant cells containing a cancer mutation to turn cancerous.

‘It’s becoming increasingly clear from work over the last two or three decades, that cancers in some cases are – to quote an old phrase – “wounds that don’t heal”,’ says Swanton. ‘There’s like a wound healing process that’s gone wrong, and what our work and others began to show is that when that wound healing process interacts with oncogenetic mutations present in normal tissues as part of the normal ageing process, that probably triggers the first invasive step.’

References

1. L. Calderón-Garcidueñas, W. Reed, R.R. Maronpot, et al, Toxicologic Pathology, 2004; DOI: 10.1080/01926230490520232.
2. L. Calderón-Garcidueñas et al, Environmental Research, 2018; DOI: 10.1080/019262304905202.
3. L. Calderon-Garciduenas et al, Toxicologic Pathology, 2003; DOI: 10.1080/01926230390226645.
4. E. Nicholls et al, The Lancet, 2022; DOI: 10.1016/S2468-2667(21)00249-8.
5. E.R. Dorsey et al, Journal of Parkinson’s Disease 2018; DOI: 10.3233/JPD-181474.
6. D. Younan et al, PLOS Med, 2022; DOI:10.1371/journal.pmed.1003893.
7. B. Krzyzanowski et al, Neurology, 2023, DOI: 10.1212/WNL.0000000000207871.
8. H. Xie et al, Journal of Affective Disorders, 2023; DOI: 10.1016/j.jad.2023.03.082.
9. D.L. Cotter et al, Environment International, 2003; DOI: 10.1016/j.envint.2023.108001.
10. L. Calderón-Garcidueñas et al, Brain and Cognition, 2011; DOI: 10.1016/j.bandc.2011.09.006.
11. E.R. Dorsey et al, Journal of Parkinson’s Disease, 2024; DOI: 10.3233/JPD-240019.