Pathophysiological Mechanisms of Cognitive Impairment and Neurodegeneration by Toxoplasma gondii Infection

Abstract

Toxoplasma gondii is an obligate intracellular parasite considered one of the most successful pathogens in the world, owing to its ability to produce long-lasting infections and to persist in the central nervous system (CNS) in most warm-blooded animals, including humans. This parasite has a preference to invade neurons and affect the functioning of glial cells. This could lead to neurological and behavioral changes associated with cognitive impairment. Although several studies in humans and animal models have reported controversial results about the relationship between toxoplasmosis and the onset of dementia as a causal factor, two recent meta-analyses have shown a relative association with Alzheimer’s disease (AD). AD is characterized by amyloid-β (Aβ) peptide accumulation, neurofibrillary tangles, and neuroinflammation. Different authors have found that toxoplasmosis may affect Aβ production in brain areas linked with memory functioning, and can induce a central immune response and neurotransmitter imbalance, which in turn, affect the nervous system microenvironment. In contrast, other studies have revealed a reduction of Aβ plaques and hyperphosphorylated tau protein formation in animal models, which might cause some protective effects. The aim of this article is to summarize and review the newest data in regard to different pathophysiological mechanisms of cerebral toxoplasmosis and their relationship with the development of AD and cognitive impairment. All these associations should be investigated further through clinical and experimental studies.

Epigenetic Manipulation of Psychiatric Behavioral Disorders Induced by Toxoplasma gondii

“…All of these factors lead to the imbalance of dopaminergic metabolism pathway. Moreover, the fact that anomalous accumulation of dopamine between synapses could cause various pathological processes such as increased dopamine concentration, synaptic structure disorder, proliferation of neural progenitor cells, and migration of neuron cells (Ortiz-Guerrero et al, 2020), thus may lead to the occurrence of psychiatric behavioral disorders. Alsaady et al (2019) also found that T. gondii could regulate the expression of dopamine b-hydroxylase (DBH) gene, which is responsible for dopamine synthesis of NE, resulting in a decrease in NE concentration in human/rat neurons that were cultured in vitro and were infected with tachyzoites, but the decrease in NE in rat brain tissue was limited in males.…”

“…However, brain cysts have been confirmed to cause persistent infection of nerve cells such as astrocytes, neurons, and microglia ( Courret et al., 2006 ). In fact, brain cysts could damage neurons, change the concentration of neurotransmitters, and interfere with the process of neuroimmune regulation in the host ( Ortiz-Guerrero et al., 2020 ). Infected mice with cerebral cysts burden showed significant behavioral disorders like diminished exploratory activity ( Barbosa et al., 2020 ), and the neurological and behavioral abnormalities are progressive and persistent in chronically infected mice that acquired primary infection in early adulthood ( Hermes et al., 2008 ).…”

“…The neuroinflammation response induced by pathogen infection may be a precipitating factor for behavioral changes in infected individuals. The activated inflammatory cytokines and chemokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and chemokines like interferon-inducible protein 10 (IP-10) and monocytic chemotactic protein 1 (MCP-1), may recruit monocytes and macrophages into the brain, or directly act on neurons, inducing apoptosis of astrocytes and glial ( Lambert et al., 2006 ; Ortiz-Guerrero et al., 2020 ), thus impairing functions of the neuron. Furthermore, altered neurotransmission levels secondary to neuroinflammation response may be responsible for the specific manipulation effects, including dopamine and other related neurotransmitters such as gamma-aminobutyric acid (GABA).…”

Comprehensive Overview of Toxoplasma gondii-Induced and Associated Diseases

“…Hence, it was concluded that chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed Alzheimer's disease, a promising approach for the treatment of this neuropathy [84]. In conclusion, the relationship of T. gondii and the development of Alzheimer's disease and cognitive impairment require further studies on human subjects and animal models [85] to elucidate the possible role of toxoplasmosis in the etiology of Alzheimer's disease.…”

Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii

“…Additionally, owing to the immature status of the immune system in the fetus and neonates, congenital T. gondii infections may result in blindness, severe neurological sequelae, and even death [24]. Moreover, there is mounting evidence correlating latent toxoplasmosis to altered behavior, as well as the development and/or exacerbation of neurodegenerative diseases and sudden-onset psychoses, such as risk-taking/reckless behavior, bipolar disorder, depression, schizophrenia, and Alzheimer's disease [25][26][27]. Thus, the vast range of susceptible hosts and multiple routes of transmission render T. gondii one of the most successful pathogens on Earth, posing an immense threat to human health.…”