Журнал болезни Альцгеймера и паркинсонизма

Абстрактный

The Intestinal Barrier in Air Pollution-Associated Neural Invol vement in Mexico City Residents: Mind the Gut, the Evolution of a Chan ging Paradigm Relevant to Parkinson Disease Risk

Lilian Calderón-Garcidueñas, Angélica Gónzalez-Maciel, Aristo Vojdani, Maricela Franco-Lira, Rafael Reynoso-Robles, Hortencia Montesinos-Correa, Beatriz Pérez-Guillé, Partha Sarathi Mukherjee, Ricardo Torres-Jardón, Ana Calderón-Garcidueñas and George Perry

Objective: Braak et al proposal in 2003 “a putative environmental pathogen capable of passing the gastric epithelial lining might induce α-synuclein misfolding and aggregation” could indeed be particulate matter gaining access through the most vulnerable section of the GI tract: the small bowel. This study is focused on the electron microscopy examination of tight junctions in duodenum of healthy dogs residing in one of the most polluted megacities in our continent, Mexico City Metropolitan Area (MCMA)with high concentrations of fine particulate matter (PM 2.5) and nanosize PM versus low-air pollution controls and to measure serum antibodies to tight junctions (TJ) and neural proteins in MCMA versus low air pollution exposed children.The small intestine would be a prime PM target: it has a single unattached mucus layer, particles have easy access to epithelial cells and Peyer’s patches, altering epithelial integrity and accessing the enteric nervous system.Autopsies in MCMA children v controls show extensive brainstem oxidative stress, microglial activation, and accumulation of α-synuclein, from the dorsal motor nucleus of the vagus to the substantianigrae.Air pollution targets the dorsal vagal complex in mice exposed to the polluted MCMA atmosphere. Methods: A pilot observational case-control dogs and children study of high versus low PM 2.5 exposures.We counted and evaluated the integrity of TJ’s in duodenal electron micrographs from 6 MCMA dogs (5.01 ± 1.36 years) and 4 control dogs (5.87 ± 1.50 years) and we measured by ELISA serum antibodies to tight junctions (TJ) and neural proteins in 95 MCMA versus controls (11.02 ± 3.6 years). Results: Disruption of epithelial integrity with TJ structural changes in MCMA v control dogs (p<0.0001), the major determinant of paracellular permeability characterized the MCMA dogs’ small bowel architecture. MCMA children had higher occludin-zonulin, actin, transglutaminase 3 and 6, and glutamic acid decarboxylase autoantibodies (p<0.01).Conclusion: The integrity of the gastrointestinal (GI) barrier is significantly compromised in MCMA dogs and could be altered in MCMA children as evidenced by the autoimmune response to TJ and neural proteins. The GI breakdown likely impacts neuronal enteric populations and PM could reach the vagus and the brainstem. In the setting of urban air pollution, the evolution of a changing paradigm favoring a pathogen penetrating an epithelial lining and via transsynaptic transmission reaching preganglionic parasympathetic motor neurons of the vagus nerve has to entertain particles as a potential culprit.Defining the linkage and the health consequences of the brain/ gut/ immune system interactions in urban children showing already the early hallmarks of Parkinson’s disease ought to be of pressing importance for public health, may provide a fresh insight into Parkinson disease pathogenesis and open opportunities for pediatric neuroprotection.