Abstract
In the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.
Highlights
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with core neuropathological features including the amassing of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) along with neuroinflammation and cognitive decline (Lane et al, 2018; DeTure and Dickson, 2019)
There was no recovery in performance in novel object recognition in the PSAPP/Rag2−/− mice compared to the PSAPP mice (Figure 1; Spani et al, 2015). These results indicate that natural killer (NK) cells may be more involved in ionized calcium binding adaptor molecule 1 (IBA1) activation compared to T- and B cells; this warrants further investigation with Il2rγ−/− deficient mice
These data indicate that major histocompatibility complex class II (MHCII) + /IBA1 + cells are activated by Th1 cells, potentially indicating a cooperative role between Th cells and microglia/macrophages
Summary
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with core neuropathological features including the amassing of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) along with neuroinflammation and cognitive decline (Lane et al, 2018; DeTure and Dickson, 2019). Knocking out macrophage chemokine receptor CCR2 in the Tg2576 mice, showed less accumulation of both microglia and macrophages (El Khoury et al, 2007), yet more recent studies have shown that it is microglial cells—and not infiltrating macrophages— that are surrounding the plaques (Reed-Geaghan et al, 2020) Together, these data suggest that in the AD brain, the microglia are potentially more impactful in the pathology compared to the infiltrating macrophages. When Aβ-specific Th1 cells were injected into the 5xFAD/MHCII- mice, there was no variation in overall plaque load, but the levels of IFN-γ were increased; these levels did not reach those found in the 5xFAD mice (Mittal et al, 2019) Together, these data indicate that MHCII + /IBA1 + cells are activated by Th1 cells, potentially indicating a cooperative role between Th cells and microglia/macrophages. Further work is needed to distinguish between the roles of the different types of T cells in AD and the cognitive consequences of the adoptive transfer of the T cells into the AD mouse brain and to understand AD development in a T cell-deficient environment
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