A new study published in the Journal of Alzheimer’s Disease (JAD) supports a growing body of research that links human exposure to aluminum with Alzheimer’s disease (AD). Researchers found significant amounts of aluminum content in brain tissue from donors with familial AD.
The study also found a high degree of co-location with the amyloid-beta protein, which leads to early onset of the disease.
“This is the second study confirming significantly high brain accumulation in familial Alzheimer’s disease, but it is the first to demonstrate an unequivocal association between the location of aluminum and amyloid-beta in the disease.
It shows that aluminum and amyloid-beta are intimately woven in the neuropathology,” explained lead investigator Christopher Exley, PhD, Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK.
An association between aluminum and amyloid-beta has been suggested for over 40 years. In an earlier study, brain tissue from donors in the United Kingdom diagnosed with familial AD showed significant accumulations of aluminum.
To further understand this relationship, in the current study the researchers measured aluminum in the brain tissue of a cohort of Colombian donors with familial AD who shared a specific mutation.
The mutation leads to elevated levels of amyloid-beta, early disease onset, and an aggressive disease etiology. The levels were compared with a control set of brain tissues from donors with no diagnosis of neuropathological disease.
They also used aluminum-specific fluorescence microscopy imaging to investigate the relationship between aluminum and amyloid-beta in familial AD.
The results were striking. The aluminum content of the brain tissue from donors with the genetic mutation was universally high, with 42% of tissues having a level considered pathologically significant, and the levels were significantly higher than those in the control set.
The imaging studies identified aluminum deposits in all brain tissues studied. They were predominantly co-located with amyloid-beta in senile plaques and occasionally in the brain vasculature.
Aluminum was also found separately from amyloid-beta in intracellular compartments including glia and neuronal axons.
The results strongly suggest that genetic predispositions known to increase amyloid-beta in brain tissue also predispose individuals to accumulate and retain aluminum in brain tissue.
Amyloid-beta (green fluorescence) and aluminum (orange fluorescence) in senile plaque from brain tissue of a familial Alzheimer’s disease donor Image is credited to the researchers.
“Compelling localization of aluminum with a central player in AD, amyloid-beta, strengthens the link of aluminum to the pathogenesis of AD,” commented George Perry, PhD, Professor of Biology, Semmes Distinguished University Chair in Neurobiology, University of Texas at San Antonio, and Editor-in-Chief of JAD.
“One could envisage increased amyloid-beta in brain tissue as a response to high levels of aluminum content, or that aluminum fosters the accumulation of amyloid-beta,” said Dr. Exley. “Either way, the new research confirms my resolve that within the normal lifespan of humans, there would not be any AD if there were no aluminum in the brain tissue. No aluminum, no AD.”
Human exposure to aluminium is burgeoning with consequent implications for health [1]. The neurotoxicity of aluminium in humans is well established, for example in dialysis encephalopathy [2], while the role of aluminium in other neurodegenerative diseases remains to be confirmed [3].
The aluminium content of human brain tissue has been reviewed recently [4] and subsequent studies have provided data on aluminium in human brain tissue in familial Alzheimer’s disease [5], autism [6] and multiple sclerosis [7].
Unequivocal quantitative analyses of aluminium in human brain tissue are now providing a strong basis for a role of aluminium in brain disease [8,9]. The recent development of aluminium-specific fluorescence microscopy now provides a relatively simple and unequivocal method of visualising aluminium in human brain tissue [10].
It has been used successfully to identify the location of aluminium in brain tissue in sporadic Alzheimer’s disease, familial Alzheimer’s disease, autism and multiple sclerosis [5,6,7,10]. Herein, we returned to a case of cerebral amyloid angiopathy (CAA) with coincident very high levels of brain aluminium [11] to identify the location of aluminium in these tissues using aluminium-specific fluorescence microscopy.
The results are perhaps surprising in light of what was originally proposed.
Discussion
Application of aluminium-specific fluorescence microscopy [10] confirmed the high content of aluminium in brain tissue in this case [11], as previously reported. A surprising feature was that deposits of aluminium were predominantly intracellular and located in grey and white matter across all four main lobes and in the hippocampus (Figure 1, Figure 2, Figure 3 and Figure 4). This is unusual because previous research identifying the location of aluminium in brain tissue in Alzheimer’s disease showed aluminium to be predominantly extracellular and associated with cellular debris [5]. This predominantly extracellular location of brain tissue aluminium was also observed in the only other ‘Camelford brain’ investigated to date [10]—a case of sporadic, early-onset Alzheimer’s disease that was also characterised by some unusual neuropathology [12].
While some aluminium was intraneuronal (Figure 1), most aluminium deposits were identified in non-neuronal cells including what appeared to be microglia, astrocytes, lymphocyte-like cells and cells lining the choroid plexus (Figure 5, Figure 6, Figure 7, Figure 8 and Figure 9). The predominantly intracellular and non-neuronal distribution of aluminium observed herein has previously only been observed in brain tissue in individuals who died with a diagnosis of autism [6].
We also confirmed, using Congo red and polarised light, the previous observation of severe, sporadic β amyloid angiopathy. Amyloid was not deposited as senile plaques, though numerous spherulites showing apple-green birefringence were identified [13].
We had expected to find the co-localisation of aluminium and β amyloid angiopathy in these tissues but, without exception, this was not the case. Aluminium and amyloid deposits were distinct from one another with no clear examples of co-localisation (Figure 9).
These are the first images of aluminium in brain tissue in a known case of CAA without significant Alzheimer’s disease pathology.
The predominance of aluminium in microglia, astrocytes, lymphocytes and cells lining the choroid plexus has all the hallmarks of an inflammatory condition and supports recent observations of CAA associated with inflammation [14]. It may also support a peripheral, outside of the central nervous system, origin for CAA [15] in this case.
While we know that the individual in this case was exposed to high levels of aluminium in their environment over an extended time period, we do not know if they suffered from a high body burden of aluminium.
The very high content of aluminium in their brain tissue does support a high body burden and its presence in inflammatory cells in brain tissue and the vasculature offers the possibility that aluminium was carried into the brain concomitant with brain inflammation.
The origin of putative brain inflammation in this case is unknown but could also be attributed to aluminium. The evidence presented herein supports the conclusion of the coroner in this case that aluminium was a likely contributor to her death.
There have been only two investigations of the neuropathology of brain tissue from individuals who were exposed to aluminium in their potable water at Camelford [10,11,12]. Both cases are characterised by unusual, if distinctly different, neuropathology and by decidedly different locations of coincident high levels of brain aluminium. While no conclusions can be drawn from just two cases, examinations of other Camelford cases, should brain tissue become available, are surely warranted.
Source:
IOS Press
