Abstract
Persistent inflammation has been identified as a contributor to aging-related neurodegenerative disorders such as Alzheimer’s disease. Normal aging, in the absence of dementia, also results in gradual cognitive decline and is thought to arise, in part, because of a chronic pro-inflammatory state in the brain. Toxoplasma gondii is an obligate intracellular parasite that establishes a persistent, asymptomatic infection of the central nervous system (CNS) accompanied by a pro-inflammatory immune response in many of its hosts, including humans and rodents. Several studies have suggested that the inflammation generated by certain strains of T. gondii infection can be neuroprotective in the context of a secondary insult like beta-amyloid accumulation or stroke. Given these neuroprotective studies, we hypothesized that a prolonged infection with T. gondii may protect against age-associated decline in cognition. To test this hypothesis, we infected young adult mice with either of two genetically distinct, persistent T. gondii strains (Prugniaud/type II/haplogroup 2 and CEP/type III/haplogroup 3) and monitored mouse weight, survival, and learning and memory over the ensuing 20 months. At the end of the study, we evaluated CNS inflammation and parasite burden in the surviving mice. We found that parasite infection had no impact on age-associated decline in learning and memory and that by 20 months post infection, in the surviving mice, we found no evidence of parasite DNA, cysts, or inflammation in the CNS. In addition, we found that mice infected with type III parasites, which are supposed to be less virulent than the type II parasites, had a lower rate of long-term survival. Collectively, these data indicate that T. gondii may not cause a life-long CNS infection. Rather, parasites are likely slowly cleared from the CNS and infection and parasite clearance neither positively nor negatively impacts learning and memory in aging.
Highlights
Persistent inflammation has been identified as a contributor to aging-related neurodegenerative disorders such as Alzheimer’s disease
To test if T. gondii can protect against normal aging[32] and determine if parasite strain type affects any potential protection, adult mice were infected with either of the two cyst-forming canonical strains and monitored over the course of their natural life span
Given that we had previously noted that type III– infected mice had a far lower central nervous system (CNS) parasite burden than type II–infected mice at 6 months post infection[28], we used a five-fold higher inoculation for mice infected with type III (50,000) vs type II (10,000) parasites
Summary
Persistent inflammation has been identified as a contributor to aging-related neurodegenerative disorders such as Alzheimer’s disease. Infection protected the brain against plaque deposition, with one group reporting reduced amyloid-induced memory deficits[30] Most of these studies have employed a type II T. gondii strain, though recently there has been an interest in the subtle differences that genetically distinct parasite strains may have on neuroprotection[28], behavior[22], and CNS immune responses[31]. Consistent with the lack of parasites in the CNS, by both flow cytometry and immunohistochemistry, we found no evidence of elevated neuroinflammation compared to age-matched, uninfected controls Together these data indicate that infection with either of two genetically distinct, encysting T. gondii strains does not alter age-associated changes in cognition and suggest that parasites can be fully cleared from the CNS
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