Emerging Roles of Cells and Molecules of Innate Immunity in Alzheimer’s Disease

Abstract

The inflammatory response that marks Alzheimer’s disease (neuroinflammation) is considered a double-edged sword. Microglia have been shown to play a protective role at the beginning of the disease. Still, persistent harmful stimuli further activate microglia, inducing an exacerbating inflammatory process which impairs β-amyloid peptide clearance capability and leads to neurotoxicity and neurodegeneration. Moreover, microglia also appear to be closely involved in the spread of tau pathology. Soluble TREM2 also represents a crucial player in the neuroinflammatory processes. Elevated levels of TREM2 in cerebrospinal fluid have been associated with increased amyloid plaque burden, neurodegeneration, and cognitive decline in individuals with Alzheimer’s disease. Understanding the intricate relationship between innate immunity and Alzheimer’s disease will be a promising strategy for future advancements in diagnosis and new therapeutic interventions targeting innate immunity, by modulating its activity. Still, additional and more robust studies are needed to translate these findings into effective treatments. In this review, we focus on the role of cells (microglia, astrocytes, and oligodendrocytes) and molecules (TREM2, tau, and β-amyloid) of the innate immune system in the pathogenesis of Alzheimer’s disease and their possible exploitation as disease biomarkers and targets of therapeutical approaches.

The role of TREM2 in Alzheimer’s disease: from the perspective of Tau

“…sTREM2 in plasma may be associated with other diseases, such as white matter lesions (Tsai et al, 2021). Although sTREM2 can serve as a potential biomarker for AD, sTREM2 levels alone may not be sufficient for an accurate diagnosis of AD, and sTREM2 in CSF is complexly associated with other AD biomarkers (Tamburini et al, 2023). Studies have shown that the levels of sTREM2 are positively correlated with the levels of classical CSF markers total Tau (t-Tau) and phosphorylated-Tau (p-Tau), but not with the concentration of CSF Aβ 42 (Heslegrave et al, 2016;Piccio et al, 2016).…”

“…Because TREM2 can recognize a variety of ligands closely related to AD and is one of the key regulators of microglial phenotype switching, it plays an important role in the progression of neuroinflammation (Tamburini et al, 2023). Therefore, TREM2 has been extensively studied as a potential AD biomarker.…”

The interaction of lipocalin-2 and astrocytes in neuroinflammation: mechanisms and therapeutic application

“…By releasing cytokines that can be pro-inflammatory or anti-inflammatory, and by phagocytosing or clearing harmful substances, immune cells can combat infection and injury, which affects neuroinflammation ( 48 ). Lcn-2 can influence the activation state of immune cells by binding to 24p3R and modulating the production and release of cytokines, communication molecules between cells.…”

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

“…It is predominantly attributed to central nervous system (CNS) immune cell dysfunction, particularly involving astrocytes and microglia. A large number of studies have explored the impact of sex on neuroinflammation in AD ( Guillot-Sestier et al, 2021 ; Singh, 2022 ; Cui et al, 2023 ; Tamburini et al, 2023 ). Specifically, one study that explored sex differences in microglia using post-mortem tissue from male and female AD patients revealed a noteworthy increase in the count of dystrophic microglia in AD females ( O'Neill et al, 2022 ).…”