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, 16 (1), 74

Exploiting Microglial and Peripheral Immune Cell Crosstalk to Treat Alzheimer's Disease


Exploiting Microglial and Peripheral Immune Cell Crosstalk to Treat Alzheimer's Disease

Dawling A Dionisio-Santos et al. J Neuroinflammation.


Neuroinflammation is considered one of the cardinal features of Alzheimer's disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD.

Keywords: Adaptive immunity; Alzheimer’s disease; Cytokines; Innate immunity; Microglia; Therapeutics.

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Fig. 1
Fig. 1
Factors impacting microglial phenotype in the context of homeostasis and neurodegeneration. Adult microglia are characterized by the expression of P2ry12, Cx3cr1, and Tmem119, among others. In addition to their role in immune surveillance, microglia participate in central nervous system homeostasis and are known to release neurotrophic factors that promote neuronal health. During Alzheimer’s disease pathogenesis, microglia are activated by amyloid β through binding of TLR4 and, in a TREM2 dependent manner, downregulate expression of homeostatic genes and upregulate Apoe, Tyrobp, Trem2, and other genes, adopting the disease-associated microglia (DAM) program. DAM are effective at containing and phagocytosing amyloid β plaques. At the same time, DAM cease their neuroprotective functions and release neuroinflammatory factors such as IL-1β and TNFα that are directly damaging to neurons and lead to tau phosphorylation and subsequent cognitive decline. In addition to local factors, the peripheral immune system can modify these responses and induce the DAM program, indicating that this is a potential target through which the homeostatic and inflammatory balance can be modulated and perhaps used to promote beneficial outcomes in AD

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