Synergistic induction of AD pathology by APOE and DDT/DDE: environmental and genetic component to neurodegenerative disease
Creators: name: Morris, Ayeshia Debbie-Ann
Publisher: name: No Publisher Supplied
Year: 2022

description: Alzheimer’s Disease is associated with numerous factors that have been found to increase an individual’s risk for developing the disease. Some of these risks are avoidable, including exposure to environmental factors, or unavoidable including aging or genetic make-up. The importance of Apolipoprotein E (APOE) and its role in altering the risk of developing AD have been intensively investigated. The E4 allele of the APOE gene is the greatest single contributor, leading to a two-to-three-fold risk increase in AD. The E4 allele leads to induction of Amyloid Precursor Protein (APP) expression in neurons and in turn alters the amount of amyloid-beta (Aβ) that accumulates in the extracellular space. To study the individual effects of the E4 variant, independent of the other variants, CRISPR/Cas9 and lentiviral transduction were utilized to generate hemizygous E3/- and E4/- induced pluripotent stem cells (iPSCs) which could be differentiated into induced neurons (iNs) and induced astrocytes (iAs). The pesticide dichlorodiphenyltrichloroethane (DDT) is an environmental risk factor for AD, with persistent bioaccumulation and elevated serum levels of its metabolite, dichlorodiphenyldichloroethylene (DDE) in AD patients even after it was banned in the U.S. fifty years ago. DDT holds open the voltage gated sodium channels leading to hyperexcitability of the nervous system, but its actions, along with the effect of DDE, have not been well studied in humans. Isolation of the APOE variants, generated using the as described above, provided an efficient way to assess the combinatory effects of genetic and environmental risks for AD.There have been few studies on whether DDT and DDE affects the human nervous system. We found that acute (≤ 6 hr) or chronic (≥ 24 hr) exposure to DDT and DDE resulted in alteration of the electrophysiological properties of mammalian neurons. Membrane depolarization was induced following toxicant exposure and firing effects observed from short-term or immediate exposure could be reversed after 5 mins for DDT and 15 mins for DDE when compounds were washed out. However, long-term/chronic exposure resulted in long lasting alterations, with both toxicants resulting in a shift in the resting membrane potential (RMP) +10 mV. More importantly, DDE induced neuronal firing after prolonged exposure while DDT only produced shifts in the RMP. The ability for DDE to exert its toxicity after prolonged exposure as well as requiring additional time for reversing its effects after acute exposures, shows, for the first time, that the DDE metabolite can alter the physiology of human neurons. Although the toxicants were not found to directly induce APOE protein expression individually, these two factors have been shown to contribute to the development or potentiation of AD. Previous evidence showed that individuals with the E4 variant of APOE genotype and DDE accumulation in their blood serum exhibited more cognitive impairment when compared to AD patients who were non-carriers of the E4 variant. Therefore, we determined that exposure to these compounds along with APOE E4 potentiated hallmarks of AD pathology by increasing amyloid precursor protein (APP) and phosphorylated Tau (pTau) expression and amyloid beta 40 and 42 peptide (Aβ40/42) secretion. Interestingly, induction of APP, pTau, and Aβ40/42 were greater with DDE exposure compared to the vehicle group by approximately 2-fold for APP and pTau and 4-fold for amyloid beta; solidifying the dangers of what was once assumed the safer of the two compounds. Literature suggests that DDT, DDE and APOE can independently alter Ca²⁺ homeostasis in neurons. The modification of this vital cation may be one mechanism by which synergism of DDT or DDE exposure and a genotype of APOE E4 can induce the risk of developing and or progressing AD. Again, our observations revealed that exposing our APOE E3/E4 humans induced neurons to DDT or DDE increased AD markers. In addition, knowing that AD patients who are carriers for APOE E4 show signs of more cognitive impairment after exposure to DDT and/or DDE. This awareness has the potential to open doors for targeting different stages of AD as well as contribute to the regulatory efforts of DDT usage; as being able to monitor or minimize exposure to this potent compound can reduce severe long-term effects.