Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer’s disease in wild-type, C57BL/6 mice

Abstract

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease associated with cognitive decline and complete loss of basic functions. The ubiquitous apicomplexan parasite Toxoplasma gondii (T. gondii) infects up to one third of the world’s population and is implicated in AD.MethodsWe infected C57BL/6 wild-type male and female mice with 10 T. gondii ME49 cysts and assessed whether infection led to behavioral and anatomical effects using immunohistochemistry, immunofluorescence, Western blotting, cell culture assays, as well as an array of mouse behavior tests.ResultsWe show that T. gondii infection induced two major hallmarks of AD in the brains of C57BL/6 male and female mice: beta-amyloid (Aβ) immunoreactivity and hyperphosphorylated Tau. Infected mice showed significant neuronal death, loss of N-methyl-d-aspartate receptor (NMDAR) expression, and loss of olfactory sensory neurons. T. gondii infection also caused anxiety-like behavior, altered recognition of social novelty, altered spatial memory, and reduced olfactory sensitivity. This last finding was exclusive to male mice, as infected females showed intact olfactory sensitivity.ConclusionsThese results demonstrate that T. gondii can induce advanced signs of AD in wild-type mice and that it may induce AD in some individuals with underlying health problems.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1086-8) contains supplementary material, which is available to authorized users.

The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease

“…Indirect evidence from animal studies has shown that the production of Aß waxes and wanes in response to immune challenge and healthy resolution. For example, Aß deposits have been noted in wild-type mice infected with Chlamydia pneumoniae (Little et al, 2004 , 2014 ; Boelen et al, 2007 ), HSV1 (Wozniak et al, 2007 ), pseudorabies virus (Tanaka and Nagashima, 2017 ), or Toxoplasma gondii (Torres et al, 2018 ), while transgenic-AD mice infected with Porphyromonas gingivalis showed increased Aß deposition (Ishida et al, 2017 ). Notably, Aß returned to normal levels after the C. pneumoniae infection had resolved.…”

LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

“…Cytokines including IL--6 and TNFα, that are characteristic of neuroinflammation, reduce the clearance of misfolded proteins such as Aβ and tau [44, 78--80]. T. gondii infection, which also results in elevated IL--6 and TNFα, induces Aβ deposition and tau hyperphosphorylation that are associated with behavioral deficits in mice [25,38]. Interestingly, one mechanism by which T. gondii evades clearance is by inhibiting autophagy [81,82], and suppression of autophagy is sufficient to induce neurodegeneration [83,84].…”

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

“…A previous comprehensive systems analysis found that T. gondii infection modified pathways involved in epilepsy and neurodegenerative diseases [219], and a recent meta-analysis concluded that T. gondii infection is a risk factor for AD [220]. There is also preclinical evidence suggesting that T. gondii infection promotes the development of epilepsy and AD in rodents [208,221,222]. On the other hand, a case-controlled study involving 99 epilepsy patients and 99 patients without epilepsy found no association between T. gondii infection and epilepsy [223].…”