Early insight into the potential contribution of aluminum to neurodegeneration - A tribute to the research work of Robert D. Terry, Igor Klatzo, Henryk M. Wisniewski and Donald R.C. Mclachlan

Abstract

The first successful attempt to obtain purified aluminum metal was accomplished by the Danish physicist and chemist Hans Christian Orsted in 1824, however it was not until about ~140 years later that aluminum's capacity for neurological disruption and neurotoxicity was convincingly established. The earliest evidence of the possible involvement of this biosphere-rich metallotoxin in Alzheimer's disease (AD) originated in the early-to-mid-1960's from animal and human research investigations that arose almost simultaneously from independent laboratories in the United States and Canada. This short communication pays tribute to the pioneering research work on aluminum in susceptible species, in AD animal models and in AD patients by the early investigators Drs. Robert D. Terry, Igor Klatzo and Henryk M. Wisniewski with special acknowledgement to the late Dr. Donald RC McLachlan, and their contemporary physician-scientist colleagues and collaborators. Together these researchers established the groundwork and foundation towards our understanding of the potential contribution of aluminum to progressive, age-related and lethal neurodegenerative diseases of the human central nervous system.

Figure 1

The Alzheimer’s disease (AD) researchers pictured above originally proposed a role for aluminum in the production of neurofibrillary tangles (NFT) and neurofibrillary degeneration in AD, with evidence largely derived from studies in experimental animal models of NFT production and a progressive aluminum-induced neurofibrillary degeneration in these animal models; their affiliations, major research interests and lifespans are given in the caption below their photo; interestingly domesticated cats (Felis catus) and rabbits (Oryctolagus cuniculus) were found to be far more sensitive to aluminum neurotoxicity and proved far superior models for experimental NFT production and genetic alterations than the common rat (Rattus rattus) or the brown rat (Rattus norvegicus) [–8]; their initial observations not only provided a series of suitable and experimentally-defined animal models for analyzing the effects of aluminum neurotoxicity in vivo, but also provided initial evidence for a species susceptibility to aluminum neuro-intoxication [–19]. Further, R.D. Terry, H.M. Wisniewski and I. Klatzo provided the very first evidence of the accumulation of NFT and neurofibrillary degeneration in cats and rabbits subjected to experimental aluminum encephalopathy, however, the geometry of the aluminum-induced and experimentally produced NFT in these aluminum-sensitive mammals were not identical to those found in human AD; after 8 additional years of intensive research and a more thorough and refined analysis of the pathogenic roles for aluminum in inducing AD-type change, including aluminum-induced genetic, epigenetic and chromatin structural changes, D.R.C. McLachlan’s laboratory was first to propose a causative, or strong contributory role, for aluminum in AD both in senile plaque (SP) and NFT formation and later, in driving changes in gene expression similar to those observed in AD. That laboratory further suggested in 1973 that ‘Neurofibrillary degeneration is an important pathological finding in senile and presenile dementia of the AD-type; experimentally, aluminum induces neurofibrillary degeneration in neurons of higher mammals; and aluminum concentrations approaching those used experimentally have been found in some regions of the brains of patients with AD [–22].