CD4+ effector T cells accelerate Alzheimer's disease in mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb-KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.

Machhi J ，Yeapuri P ，Lu Y ，Foster E ，Chikhale R ，Herskovitz J ，Namminga KL ，Olson KE ，Abdelmoaty MM ，Gao J ，Quadros RM ，Kiyota T ，Jingjing L ，Kevadiya BD ，Wang X ，Liu Y ，Poluektova LY ，Gurumurthy CB ，Mosley RL ，Gendelman HE ... -  《Journal of Neuroinflammation》

IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease.

Browne TC ，McQuillan K ，McManus RM ，O'Reilly JA ，Mills KH ，Lynch MA ... -  《-》

Amyloid-β specific regulatory T cells attenuate Alzheimer's disease pathobiology in APP/PS1 mice.

Yeapuri P ，Machhi J ，Lu Y ，Abdelmoaty MM ，Kadry R ，Patel M ，Bhattarai S ，Lu E ，Namminga KL ，Olson KE ，Foster EG ，Mosley RL ，Gendelman HE ... -  《Molecular Neurodegeneration》

Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells.

Yang Y ，He Z ，Xing Z ，Zuo Z ，Yuan L ，Wu Y ，Jiang M ，Qi F ，Yao Z ... -  《Journal of Neuroinflammation》

Age- and sex-related differences of periodontal bone resorption, cognitive function, and immune state in APP/PS1 murine model of Alzheimer's disease.

The existence of an interconnected mechanism between cognitive disorders and periodontitis has been confirmed by mounting evidence. However, the role of age or sex differences in this mechanism has been less studied. This study aims to investigate sex and age differences in the characterization of periodontal bone tissue, immune state and cognitive function in amyloid precursor protein/presenilin 1(APP/PS1) murine model of Alzheimer's disease (AD). Three- and twelve-month-old male and female APP/PS1 transgenic mice and wild-type (WT) littermates were used in this study. The Morris water maze (MWM) was used to assess cognitive function. The bone microarchitecture of the posterior maxillary alveolar bone was evaluated by microcomputed tomography (micro-CT). Pathological changes in periodontal bone tissue were observed by histological chemistry. The proportions of helper T cells1 (Th1), Th2, Th17 and regulatory T cells (Tregs) in the peripheral blood mononuclear cells (PBMCs) and brain samples were assessed by flow cytometry. The learning ability and spatial memory of 12-month-old APP/PS1 mice was severely damaged. The changes in cognitive function were only correlated with age and genotype, regardless of sex. The 12-month-old APP/PS1 female mice exhibited markedly periodontal bone degeneration, evidenced by the decreased bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and bone mineral density (BMD), and the increased trabecular separation (Tb.Sp). The altered periodontal bone microarchitecture was associated with genotype, age and females. The flow cytometry data showed the increased Th1 and Th17 cells and the decreased Th2 cells in the brain and PBMC samples of 12-month-old APP/PS1 mice, compared to age- and sex-matched WT mice. However, there was no statistical correlation between age or sex and this immune state. Our data emphasize that age and sex are important variables to consider in evaluating periodontal bone tissue of APP/PS1 mice, and the cognitive impairment is more related to age. In addition, immune dysregulation (Th1, Th2, and Th17 cells) was found in the brain tissue and PBMCs of APP/PS1 mice, but this alteration of immune state was not statistically correlated with sex or age.

Chen H ，Liao Y ，Zhang X ，Shen H ，Shang D ，He Z ，Zhou W ，Song Z ... -  《Journal of Neuroinflammation》