Air pollution, glymphatic impairment, and Alzheimer's disease

Abstract

Epidemiological evidence demonstrates a link between air pollution exposure and the onset and progression of cognitive impairment and Alzheimer's disease (AD). However, current understanding of the underlying pathophysiological mechanisms is limited. This opinion article examines the hypothesis that air pollution-induced impairment of glymphatic clearance represents a crucial etiological event in the development of AD. Exposure to airborne particulate matter (PM) leads to systemic inflammation and neuroinflammation, increased metal load, respiratory and cardiovascular dysfunction, and sleep abnormalities. All these factors are known to reduce the efficiency of glymphatic clearance. Rescuing glymphatic function by restricting the impact of causative agents, and improving sleep and cardiovascular system health, may increase the efficiency of waste metabolite clearance and subsequently slow the progression of AD. In sum, we introduce air pollution-mediated glymphatic impairment as an important mechanistic factor to be considered when interpreting the etiology and progression of AD as well as its responsiveness to therapeutic interventions.

Keywords: CSF; aging; amyloid plaques; neurodegeneration; ultrafine particles.

Fig. 1:. Airborne particulate matter exposure and entry into the brain.

Left: Small airborne particles (UFP) generated for instance via combustion processes can translocate to the brain directly after depositing in the nose and uptake by olfactory mucosal nerves. Right, middle: UFP also deposit efficiently in the gas-exchange region of the lung, where they can translocate to local lymph nodes. UFP that can make their way from the lung to the bloodstream are distributed to other distant organs in the body including the brain. Right, top: Inhaled UFP can induce systemic inflammation and may interact directly with the endothelial cells of the BBB, disturbing tight junctions and gaining access to the brain parenchyma. Right, bottom: A fraction of UFP in the gastrointestinal tract is also able to make its way to the bloodstream or mesenteric lymphatics via villi and/or breaching the Peyer’s patches.

Fig. 2:. A fluid flow impairment as a result of PM exposure may exacerbate AD.

Left: Under normal physiological conditions, CSF moves within the periarterial spaces, exchanges with the interstitial fluid and is recollected by peri-venous spaces. In this path, CSF carries metabolic waste, Aβ, excessive pTau, and UFP and clears them from the brain. This process of waste clearance is facilitated by AQP4 at the astrocyte end feet. Macrophages within the peri-vascular spaces add an additional layer of surveillance; non-desired particles are either engulfed by macrophages or flushed out by CSF flow. Right: Long-term exposure to UFP putatively, results in increased amounts of solid particles within perivascular spaces, the polarized expression of astrocyte AQP4 decreases, and peri-vascular spaces narrow, impairing the clearance of metabolites and exogenous particles from the brain. Long-term fluid retention or malabsorption likely contributes to the enlargement of the periarterial spaces [113]. Direct binding of UFP with the protofibrils may facilitate the formation of Aβ plaques along the vasculature [–116]. After breaching epithelial barriers, UFP may enter the brain parenchyma, which could initiate neuroinflammation, and further decrease the process of efflux of Aβ.

Fig. 3:. Multi-level effects of UFP in the brain and exacerbation of AD.

We propose that UFP, upon inhalation, trigger multiple reactions: olfactory bulb inflammation and neuroinflammation, BBB impairment, and perivascular changes including increased thickness of basement membrane and fragmentation [etc.]. These changes result in impaired glymphatic function, which is further augmented by peripheral inflammation, endothelial cell damage as well as impaired breathing related to sleep or circadian disturbances. Impairment of glymphatic function not only increases the amounts of waste and Aβ in the brain, but may facilitate protein aggregation which worsens over time and contributes to neurodegeneration and dementia in AD and related disorders.

Figure I:. Diagram outlining glymphatic clearance of waste and Aβ.

Aβ40/42 is produced within the brain parenchyma, and is cleared via peri-venous efflux as well as cervical lymphatic vessels. The periarterial inflow of cerebrospinal fluid that exchanges with interstitial fluid is facilitated by astrocytic AQP4 water channels. Similarly, outflow/recycling of CSF containing both soluble and insoluble waste metabolites occurs via meningeal and cervical lymphatic vessels to the lymph nodes.