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Letters to the Editor


I read with interest the Society for Neuroscience meeting report that in mice, the loss of tau function leads to increasing iron accumulation in brain the, causing Parkinson disease-like symptoms (“Loss of Tau Increases Iron, Causes Parkinsonism,” Jan. 6;

Aluminum appears to interact with tau, causing aluminum-hyperphosphorylated tau complexes in early Alzheimer disease, according to a 2010 paper in the Journal of Alzheimer's Disease.

I find it interesting that aluminum toxicity is mediated through reactive oxygen species production and iron accumulation, the very things that are thought to lead to parkinsonism.

These findings led me to wonder whether perhaps aluminum impairment of tau function in the brain leads to accumulation of iron and reactive oxygen species in those who are susceptible to Parkinson disease, and similarly, whether the aluminum-tau interaction with tau dysfunction with subsequent abnormal trafficking of amyloid precursor protein in the cell leads to excessive amyloid beta (Abeta) production and development of Abeta plaques in individuals susceptible to Alzheimer disease.

Steven R Brenner MD

St. Louis University

St. Louis, MO


Dr. Brenner raises a hypothesis that had been explored for many years after aluminum exposure was explained as a cause of dementia in dialysis patients. The concern was also based on studies in 1965 that showed that injection of experimental animals with aluminum compounds directly to the brain induces the formation of neurofibrillary tangles (NFTs), which are principally composed of tau. Indeed some studies have identified aluminum in NFTs.

The main problem with the aluminum toxicity hypothesis of Alzheimer disease (AD) is that aluminum is not a metal ion that has any known biological purpose. The concentrations of aluminum in the blood and the brain are low (submicromolar).

My lab has, for several years, elaborated the normal biochemical interactions of the amyloid precursor protein (APP) with biological metal ions, iron, copper and zinc, whose concentrations in the brain are orders of magnitude greater than aluminum. It is now well established that zinc, which is released during glutamatergic neurotransmission, induces amyloid pathology in mouse-models of Alzheimer disease and that the amyloid plaque is a site of marked enrichment of zinc (as well as copper and iron).

Zinc, copper, and iron enrichment is observed within both plaques and tangles, but these metal ions are present in the human pathology at much higher concentrations than aluminum.

The presence of aluminum in the pathology is likely to be a product of contamination, since aluminum is hugely abundant in dust and glassware. Since the proteins implicated in AD are frequently metalloproteins that interact with biological metals (iron, copper and zinc), it is not surprising that these proteins become easily contaminated with trace concentrations of other non-biological, contaminant metals like aluminum.

While at this stage we cannot exclude a contribution of aluminum, which is indeed redox-active, to the neuropathology of AD, its potential contribution would be far outweighed by the threat posed by the more abundant biological metal ions that are trapped in the pathology. Iron and copper are redox-active and generate radical damage, so there are extensive systems to ensure that the concentrations of free copper and iron ions are minimal.

We have recently reported that APP is a ferroxidase that is responsible for lowering neuronal iron levels. In AD this activity is inhibited by zinc exchanging from extracellular amyloid deposits. These interactions are important for AD because they can be corrected by candidate therapeutic transition metal ionophores like PBT2, which target zinc and copper interaction with amyloid, but have no influence on aluminum/-PBT2 treatment for 12 weeks improved cognition in a phase 2 clinical trial of Alzheimer patients. And the drug is slated for further testing.

This most recent preliminary report that tau influences neuronal iron metabolism is consistent with our global hypothesis that AD represents a perturbance of normal metal ion regulatory systems in the brain as a result of aging. Aluminum is not subject to homeostatic regulation, and the only experiments that have induced neuropathology with aluminum have involved unnaturally high concentrations of aluminum in a toxicology paradigm.

This level of exposure is unlikely to contribute to Alzheimer or Parkinson pathology, and indeed, an analysis of the epidemiological literature has not supported aluminum exposure as a risk factor for AD. In contrast, the major proteins implicated in AD — APP, presenilin, beta-site APP cleaving enzyme 1 (BACE), and tau — have a growing number of physiological interactions with the normally abundant brain metal ions. This leads to an attractive hypothesis that failure in the metal-regulatory activities of these proteins may contribute to the onset of AD disease.

Ashley I. Bush, MD, PhD

Harvard University

Cambridge, MA

Disclosure: Dr. Bush is a paid consultant and shareholder of Prana Biotechnology Ltd, a shareholder of Cogstate Ltd, and paid consultant for Amgen.


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