Aluminum is the third most abundant element in the Earth’s crust, making human exposure to this ubiquitous metal inevitable. Despite its prevalence, aluminum has no known biological function and is not essential for human metabolism. The presence of aluminum in various environmental and commercial products has generated public health interest regarding its potential to accumulate in the body. Of particular concern is the mechanism by which aluminum bypasses the body’s protective barriers to enter the central nervous system.
Pathways of Initial Exposure and Absorption
Aluminum enters the human body through several primary routes, including the gastrointestinal tract, the respiratory system, and, to a lesser extent, the skin. For the general population, the main source of aluminum intake is oral, coming from food, drinking water, and aluminum-containing medicines like antacids.
The intestinal absorption of aluminum is low, with estimates suggesting that less than one percent of ingested aluminum is absorbed into the bloodstream. In contrast, inhaled aluminum, such as fine particles or dust, can have a slightly higher absorption rate, estimated at about 1.5 to 2%. Once absorbed, the aluminum enters the systemic circulation, where it must confront the brain’s specialized defense system.
The Blood-Brain Barrier: The Gatekeeper
The brain is protected from fluctuating blood chemistry and potentially harmful substances by a highly selective structure known as the blood-brain barrier (BBB). This barrier is formed by the endothelial cells lining the brain’s microvessels. These cells lack gaps or fenestrations and are stitched together by specialized structures called tight junctions.
These tight junctions create a seal that prevents the passive movement of most water-soluble molecules and metal ions from the blood into the brain tissue. The barrier is further supported by the end-feet of astrocytes, a type of glial cell that wraps around the capillaries and helps maintain the barrier’s integrity. The primary function of the BBB is to regulate the brain’s internal environment, allowing specific nutrients to pass while actively excluding toxins. Aluminum cannot simply diffuse into the brain and must employ specific biological strategies for entry.
Hijacking Transport Systems to Enter the Brain
To successfully cross the blood-brain barrier, aluminum relies on molecular mimicry and the utilization of existing transport pathways designed for beneficial substances. The most significant mechanism involves aluminum’s chemical similarity to the essential nutrient iron (Fe3+). In the bloodstream, aluminum rapidly binds to transferrin, the body’s primary iron carrier.
This aluminum-transferrin complex exploits the brain’s iron delivery system, known as receptor-mediated transcytosis. Transferrin receptors, abundant on the BBB’s endothelial cells, recognize the aluminum-bound transferrin. The receptor then engulfs the complex in a small vesicle, transports it across the endothelial cell, and releases the aluminum into the brain interstitial fluid.
A second mechanism involves the formation of a complex between aluminum and small chelating agents naturally present in the blood, most notably citrate. Aluminum citrate is a small, uncharged molecule that can be transported across the barrier by specific carrier systems. These include System Xc-, an amino acid antiporter, or the monocarboxylic acid transporter (MCT). Aluminum citrate appears to be a substrate for System Xc-, allowing it to be carried into the brain endothelial cells. The MCT may also contribute to entry depending on the concentration gradient, though it is primarily involved in efflux.
Retention and Localization in Neural Tissue
Once aluminum has successfully navigated the blood-brain barrier, it exhibits a high affinity for binding to various components within the neural tissue, leading to accumulation. The redistribution of aluminum out of the brain is slow compared to its rate of entry, which accounts for its long-term persistence. The brain lacks the robust clearance mechanisms, such as the kidney’s filtration system, that eliminate absorbed aluminum from the rest of the body.
Aluminum tends to localize in specific brain regions, with the hippocampus and temporal lobes frequently reporting higher concentrations. Within these regions, the metal is found sequestered within specific cell types, including both neurons and glial cells, particularly astrocytes and microglia.
In neurons, aluminum is often observed co-localizing with various proteins, including those involved in the formation of neurofibrillary tangles. The presence of aluminum inside these long-lived cells, which have poor mechanisms for metal excretion, contributes significantly to the metal’s long biological half-life in the central nervous system. This poor clearance means that even low-level, chronic exposure can increase the brain’s total aluminum burden over a lifetime.