Impact of environmental pollutants on neurodevelopment and Alzheimer's disease (Véronique Perrier)
The contamination of our drinking water resources and food with environmental pollutants, such as pesticide residues and plastic derivatives, is a major public health issue. The discovery of the "endocrine disrupting" effect of many pesticides and chemical derivatives, challenging the toxicological principles stipulating that "dose makes the poison", raises many public concerns. Furthermore, studies on the dosage of pesticides in hair or biological fluids in humans have revealed the extent of exposure and contamination of organisms to these products.
Unlike to Parkinson's disease, the effects of chronic exposure to these environmental pollutants in the etiology or aggravation of Alzheimer's disease are not clearly identified through epidemiological studies. Thus, experimental models mimicking the contamination to pollutants are necessary to understand their effects and modes of action.
Our research focuses on the effects of fungicide residues(1-2) and plastic residues on Alzheimer's disease markers using different models (transgenic mice, cellular models). The potential role of these compounds in the etiology of Alzheimer's disease, in particular sporadic cases which are not yet elucidated, is being investigated.
Recently, researches conducted in our group on J20 transgenic mice (hAPPSw/ind) showed an aggravation of astrogliosis and microglial inflammation, as well as vascular amyloid angiopathy, when these animals were exposed to a cocktail of 3 fungicides of the anilinopyrimidine family(2). We are currently investigating whether similar effects also occur in other models of transgenic mice.
On the other hand, exogenous factors could be at the origin of neurodegenerative pathologies later in life, by altering the development of the brain during the foetal period. We have set up models of mother-child fetal contamination in the laboratory. We study the effects of in utero exposure to low-doses of pollutants on brain development(3). Analyses in electrophysiology are currently being carried out to highlight possible changes in synaptic transmission. In utero electroporation techniques and the use of fluorescent "Magic markers" in collaboration with Dr. K. Loulier, (Corticogenesis team, INM, Montpellier), will enable us to identify potential imbalances between neuronal or glial populations in the different structures of the brain.
(1) Lafon PA., Imberdis T., Wang Y., Torrent J., Huetter E., Alvarez-Martinez M.T., Chevallier N., Givalois L., Desrumaux C., Liu J. and Perrier V. (2018) Low doses of bioherbicide favour prion aggregation and propagation in vivo. Sci. Rep, 8:8023.
(2) Lafon PA., Wang Y., Arrango-Lievano M., Torrent J., Salvador-Prince L., Mansuy M., Mestre-Francès N., Givalois L., Liu J., Mercader J.V., Jeanneteau F., Desrumaux C. and Perrier V. (2020) Fungicide residues exposure and β-amyloid aggregation in a mouse model of Alzheimer’s disease. Environ Health Perspect, 128(1):17011.
(3) Wang Y., Lafon P.A., Crozet C., Relano gines A., Trousse F., Liu J. and Perrier V. (2020) Prenatal exposure to low doses of anilinopyrimidine fungicides disrupts neurogenesis in neonates and predisposes to the onset of Alzheimer’s disease. Submitted.
Impact of environmental pollutants on Aβ assembly and consequences for Alzheimer's disease (Joan Torrent)
We are interested in understanding the fundamental molecular events governing the misfolding and aggregation of proteins into highly ordered amyloid fibrils. Close to 50 different human proteins have been found to form these proteinaceous assemblies that are thought to be responsible for the pathogenesis of various diseases, including neurodegenerative disorders such as Alzheimer’s disease.
Specifically, our research is aimed at identifying environmental factors (i.e. pollutants) as external influences that can affect the amyloidogenic process, with a particular emphasis on those having an impact on the amyloid filbril morphology and neurotoxicity, as well as on the autocatalytic propagation of fibrils throughout the brain.
The rationale for this is that pollutants are found throughout the environment and that human exposure to these widespread chemicals is growing at exponential rates. Although the knowledge on the adverse effects on human health is very limited, difficult to assess and still controversial, the neurological long-term problems that they can cause are especially alarming. Epidemiological studies as well as laboratory-based findings of pollutants effects in animals show that they could be manifested by not only an increased incidence of neurodegenerative diseases, but also by increasingly lower ages of their onset.
We study amyloid formation from every angle, combining different approaches such as biochemistry and microscopy, as well as cell cultures and transgenic mice models. Since treatment for neurodegenerative diseases is lacking, our research opens in this way two strategies for prevention: i) a primary prevention strategy based on identifying pollutants modulating amyloid formation, structure and biological activity; and ii) a secondary prevention strategy based on the early detection of misfolded proteins, as a biomarker that reflects earlier exposures to a polluted environment. To do this, we develop seeding amplification assays to detect misfolded protein assemblies (oligomers and/or amyloid fibrils) by their capacity to trigger the aggregation of the monomeric protein in a prion-like mechanism of propagation.