Brain Burdens of Aluminum, Iron, and Copper and their Relationships with Amyloid-β Pathology in 60 Human Brains

Abstract

The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer’s disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloid-β deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu:Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that, in individuals with moderate to severe amyloid pathology, low brain copper is a predisposition to developing dementia.

What is the risk of aluminium as a neurotoxin?

“…Evidence is burgeoning that once a potentially toxic threshold of aluminium is reached, other factors then come into play as to whether this burden of aluminium is neurotoxic. For example, recent research has highlighted relationships between brain metal content, amyloid pathology and AD such that it was not the absolute brain aluminium content which predicted disease, but the ratio of copper-to-aluminium in the tissue [9]. In individuals demonstrating moderate-tosevere amyloid pathology when the ratio of copper-to-aluminium in brain tissue exceeded 20, the incidence of AD was predicted to be lower.…”

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

“…However, AD is also associated with other metal imbalances such as major depression of copper levels and the issue of causality remains elusive (Akatsu et al, 2012;Exley et al, 2012).…”

Copper in Alzheimer’s disease: Implications in amyloid aggregation and neurotoxicity

“…intracellular copper promotes amyloidogenic processing of APP, that is, the protease activity of β-secretase (BACE1) and γ-secretase (presenilin-dependent multiprotein complex), leading to the fragments Aβ 40 and Aβ 42 , while α-secretase -which cleaves between residues 16 and 17-is hindered (Fig. 1).…”

“…1 Apart from APP, it has also been demonstrated that tau and β-secretase bind copper. 2 The fragments Aβ 40 and Aβ 42 are the two principal variants of the amyloid peptide in humans. Aβ 42 is more toxic and more prone to fibrillize, while Aβ 40 is less toxic but is produced 10 times more than Aβ 42 .…”

“…2 The fragments Aβ 40 and Aβ 42 are the two principal variants of the amyloid peptide in humans. Aβ 42 is more toxic and more prone to fibrillize, while Aβ 40 is less toxic but is produced 10 times more than Aβ 42 . Some authors point to the importance of the ratio Aβ 42 /Aβ 40 for the generation of elusive toxic Aβ species.…”