Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis

Toxoplasma gondii is a protozoan parasite that infects about a third of human population. It is generally believed that in immunocompetent hosts, the parasite infection takes usually asymptomatic course and induces self-limiting disease, but in immunocompromised individuals may cause significant morbidity and mortality. T. gondii uses sulfated proteoglycans for host cell invasion and sulfated sugars on the surface of host cells may functions as key parasite receptors. Patients with autism spectrum disorders (ASD) have many inborn or acquired abnormalities of metabolism, including impaired sulfation and sulfoxidation. The impaired sulfation of dehydroepiandrosterone (DHEA) to DHEA-S affected normal development of various brain functions because DHEA-S inhibited vascular neuroinflammation in ASD individuals probably caused by cerebral toxoplasmosis (CT). Treatment of endothelial cells with DHEA-S dramatically inhibited the TNF-α-induced activation of NF-κB, an inflammatory transcription factor, and increased protein levels of the NF-κB inhibitor, IκB-α. A significant decrease in sulfation capacity found during pregnancy compared with post partum probably reflect a defense reaction of the host due to increased production of proinflammatory cytokines associated with frequent and widespread infection with this parasite. This suggestion may be supported by the finding that TNF and IL-1 mediated inhibitory effect of lipopolysaccharide on DHEA sulfotransferase mRNA level in Hep3B human hepatoma cells. It seems however that the impaired sulfation and sulfonation may be also beneficial for the host because lack or a markedly diminished anionic charge of the host cells associated with this event did not promote binding to the negatively charged outer leaflet of T. gondii plasma membranes. Phosphorylation of the parasite and/or host proteins is also of great importance in the process of T. gondii–host cell interaction. Furthermore, the increased male to female ratio characteristic for autistic participants most likely resulted from significantly increased testosterone levels associated with congenital T. gondii infection. It was demonstrated that the parasite, aging and dietary restriction have been able to induce DNA breakage, therefore one may suggest that such an epigenetic mechanism play an important role in development of Down syndrome (DS). Several data may support this notion: (a) autism occurs 10 times more often in children with trisomy 21 than in the general population, (b) the parasite can be transmitted by semen and ovum, (c) autistic children exhibit impaired DNA methylation capacity, and (d) T. gondii affect chromatin structure and may cause dysregulation of the host cell cycle. Alzheimer disease (AD) also may be caused by CT because this abnormality is more prevalent in women, characterizes with a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur that manifest as a decreased plasma levels of DHEA-S, and has marked immune irregularies in part due to aging. Moreover, chronic neuroinflammation characteristic for AD and DS individuals is associated with vascular lesions, patients with AD have increased levels of DNA breaks in the cerebral cortex, markedly enhanced production of proinflammatory cytokines, reactive oxygen species, and lipid peroxidation, disturbances in glucose metabolism, and irregularities in hypothalamic–pituitary axis. It must be noted that similar metabolic and endocrine disturbances have been reported also in humans and mice with chronic toxoplasmosis. Overproduction of IFN-γ and other proinflammatory cytokines associated with persistent neuroinflammation resulted in neurodegeneration and induced amyloid-β production also in DS, as well as accounted for cognitive impairment. Because bradyzoites and sporozoites throughout their life cycle accumulate large amounts of crystalline storage polysaccharide granules analogous to amylopectin within the cytoplasm and are able to build more complex macromolecules, they may be at least in part responsible for the production of amyloid-β senile plaques. Moreover, it seems that the accumulation of iron in senile plaques reflect a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites. Finally, the beneficial effects of ibuprofen in the patients with AD that restored cellular immunity, decreased production of proinflammatory cytokines, NO, amyloid-β, reduced lipid peroxidation and free radical generation, were consistent with the suggestion that congenital and/or acquired chronic latent CT play an important role in development of these types of neurodegeneration.