Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer’s Disease Model Mice

Abstract

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer’s disease (AD) worsens with the accumulation of amyloid β (Aβ) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aβ plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aβ plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aβ plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.

Behavioral and Neuropathological Changes After Toxoplasma gondii Ocular Conjunctival Infection in BALB/c Mice

“…Transcriptome studies have indicated that homeostatic microglia gradually adopt a unique phagocytic disease-associated microglia (DAM) phenotype in neurodegenerative disease, chronic inflammation, and advanced aging ( Rangaraju et al., 2018 ). In addition, it has been demonstrated that T. gondii infection induces homeostatic microglial proliferation that reduces Aβ plaque burden in a 5XFAD AD mouse model ( Shin et al., 2021 ), suggesting a sustained supply of homeostatic microglia may help in the resolution of Alzheimer’s and other prion-like neurodegenerative disorders.…”

Comprehensive Overview of Toxoplasma gondii-Induced and Associated Diseases

“…In the infected group, a significant decrease in the amyloid plaque burden concurrent with an extensive proliferation of homeostatic microglial proliferation and an increased number of plaque-associated microglia were observed. 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.…”