Abstract
BackgroundAlzheimer’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.MethodsIn 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.ResultsThe 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.ConclusionsThese 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.Graphical
Highlights
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
Flow cytometric analysis for intracellular cytokines revealed that activated Amyloid beta (Aβ)-Type 1 T helper (Th1) cells expressed pro-inflammatory cytokines, interferon gamma (IFNγ) (44.1%) and tumor necrosis factor alpha (TNFα) (52.3%), and expressed nuclear transcription factor T-box expressed in T cells (Tbet) (85.6%)
To further confirm the cellular phenotype of Aβ-Effector T cell (Teff), extracellular cytokine release was assessed by the immunoblot staining, which showed that Aβ-Th1 cells selectively secreted Interferon gamma (IFNγ), while Aβ-Type 17 Th (Th17) cells secreted higher levels of interleukin 17 (IL17) (Fig. 1b)
Summary
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 persists and has been identified as a key disease-driving factor [2, 5] Both innate and adaptive immunity play disease-propagating roles [2, 6, 7]. Central nervous system (CNS) innate microglial cells and astrocytes are activated by the disease proteins and contribute to neuronal injuries by producing inflammatory and neurotoxic factors. These increase aberrant amyloid precursor protein (APP) cleavage, Aβ production, and tau phosphorylation [8, 9]. We posit that understanding disease-linked adaptive immunity will permit the harnessing of peripheral immune T cell responses to facilitate AD therapeutic management
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