Sessions on Monday morning at the SOT Annual meeting definitely got the meeting off to an exciting start. After Dr. Venter’s fascinating opening lecture, I had the pleasure of extending my knowledge of the etiology of Alzheimer’s disease (AD) by attending the workshop entitled “Environmental Exposures and Alzheimer’s Disease: Epidemiology, Mechanisms, and Future Strategies.” Several of the speakers provided statistics about the prevalence and future trajectory for cases of AD. For example, Dr. Nasser Zawia, University of Rhode Island, pointed out that there are currently an estimated 5 million cases of AD in the US, and 36 million worldwide. Ninety-five percent are categorized as ‘sporadic’ and are generally late in onset; 5% are believed to have a strong genetic association and are more likely to be early in onset. Dr. Zawia also provided two additional fascinating statistics: by 2025, it is predicted that there will be 7.5 million cases in the US, and ~300 drugs have failed to provide a benefit. He then provided a provocative hypothesis that brain aging begins at birth and that there may be a developmental basis for AD. His own work in non-human primates and mice suggests that transient, early-life exposure to lead may eventually result in AD onset. His lab has done work to investigate potential epigenetic mechanisms for these observations, and has shown that lead has effects on both methylation and acetylation endpoints in mice and non-human primates.
Dr. Marc Weisskopf, an epidemiologist from the Harvard School of Public Health provided some important caveats about recruiting and participation in epidemiologic studies. Given that we learned from Dr. Venter that the best animal model for studying human diseases is humans, the thought exercise provided was very valuable. Although the bulk of his talk was focused on cardiovascular disease to illustrate his points, he taught us about a method to reconstruct early life vs. adult exposure to lead in humans. This is important as retrospective measures to reconstruct lead exposure often rely on job title, but may miss other important sources of lead exposure, such as environmental and exposure to lead paint in homes, and also likely fails to account for timing of exposure. Working with a number of collaborators, Dr. Weisskopf described a recently-developed method called laser ablation, which can be used to collect tooth enamel vs. dentin for lead analysis. This is an important distinction as enamel is formed in early childhood (before age of 5 yr), so it can be ‘mined’ as an indicator of childhood lead exposure. Importantly, based on the location and concentration of lead in the samples captured by laser ablation, the amount of lead exposure and the timing can be determined. Tooth dentin continues to grow into adulthood, so a finding of lead in dentin indicates adult lead exposure has occurred. The studies can be conducted on teeth shed from children, teeth extracted from adults, and post mortem collection. These studies should help to determine the timing of lead exposure as a risk factor for AD development.
Drs. Anumantha Kanthasamy, Iowa State University, and Jason Richardson, Woods Hole, provided some mechanistic studies showing potential relationships between metals (in particular manganese) and pesticides (especially DDT and its metabolites) on the development of neurodegenerative disorders. Dr. Kanthasamy began with a discussion of protein aggregation as the basis of both Parkinson’s disease (PD) and AD. He presented data showing that prion protein has metal binding sites, and that low, normal physiological concentrations of a-synuclein can be protective against protein aggregation. He also showed that manganese promotes cell-to-cell transmission of a-synuclein, which is associated with motor deficits in mice. He further showed that when injected into the ventricles of the mouse brain, these exomes promoted protein aggregation and motor deficits in mice.
Dr. Richardson began with a review of a 2009 publication from his lab, showing that elevated serum levels of pesticides was associated with a risk of PD. Significantly, a 2014 paper from his group also showed an association between elevated pesticide levels and risk of AD. This paper carefully evaluated a number of factors, including apolipoprotein E (ApoE) genotype. ApoE exists in three forms in humans (ApoE2, 3, and 4), with the ApoE4 form having an association with overall lower cognition, and a significant genetic risk of development of AD. While the sample size was relatively small, the results clearly showed that serum DDE levels were 4X higher in serum of AD cases, compared to controls, and this association held even after adjusting for ApoE genotype. DDE is a major metabolite of DDT, and the mechanism of neurotoxicity of DDT involved prolonged opening of sodium channels. He then asked what the functional association might be between DDT/DDE and AD. Dr. Richardson showed data that revealed that neuronal depolarization results in release of amyloid precursor protein (APP), which, when cleaved, results in amyloid-beta (Ab) formation. This is significant because Ab is a major component of a pathological lesion found in the AD brain, the senile plaque. Using a neuronal cell line in vitro, he showed that 1 mM DDT upregulated both APP and ApoE gene expression, with the effect most pronounced after 48 hours of incubation. Significantly, this effect was blocked with tetrodotoxin, a sodium channel blocker. In vivo studies in mice showed that mice gavaged with 3 mg/kg DDT 10 times over a 30 day period resulted in increased expression of both APP and ApoE in the hippocampus.
This workshop reinforced hypotheses that environment, particularly environmental exposures superimposed on one or more genetic risk factors, may underlie many ‘sporadic’ cases of AD. The hypothesis that AD may arise from an early childhood exposure was new to me, and suggests, together with other data presented in the workshop, that there may be a toxic trifecta (genetic background, timing, and genetic susceptibility) that ultimately, unfortunately, culminates in AD.
This blog discusses highlights from the SOT Annual Meeting and ToxExpo Workshop “Environmental Exposures and Alzheimer’s Disease: Epidemiology, Mechanisms, and Future Strategies.”