Role of Microglia TLRs in Neurodegeneration

Abstract

Toll-like receptors (TLRs) are a group of receptors widely distributed in the organism. In the central nervous system, they are expressed in neurons, astrocytes and microglia. Although their involvement in immunity is notorious, different articles have demonstrated their roles in physiological and pathological conditions, including neurodegeneration. There is increasing evidence of an involvement of TLRs, especially TLR2, 4 and 9 in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). In this sense, their expression in microglia might modulate the activity of these cells, which in turn, lead to protective or deleterious effects over neurons and other cells. Therefore, TLRs might mediate the link between inflammation and neurodegenerative diseases. However, further studies have to be performed to elucidate the role of the other TLRs in these diseases and to further prove and confirm the pathophysiological role of all TLRs in neurodegeneration. In this article, we revise and summarize the current knowledge regarding the role of TLRs in neurodegeneration with the focus on the possible functions of these receptors in microglia.

Aging and sex: Impact on microglia phagocytosis

“…Thus, higher IRAK4 mRNA levels in microglia isolated from newborn male animals compared to female microglia are consistent with a higher capacity of male cells to internalize E. coli ‐coated bioparticles, since IRAK4 mediates upregulation of scavenger receptors (Doyle et al., 2004) by TLR2 and TLR4. These receptors can recognize both microbial patterns and danger‐associated molecular patterns and mediate brain injury‐induced inflammation and microglia phagocytosis under pathological conditions (Fiebich, Batista, Saliba, Yousif, & de Oliveira, 2018). In addition, higher mRNA levels of CD206, MSR1, and Scarb1 in microglia isolated from newborn female brains are compatible with the increased basal nonspecific and neural debris phagocytosis of these cells, given that these genes encode for scavenger receptors that are important in the innate host response to bacterial and fungal pathogens (Husemann, Loike, Anankov, Febbraio, & Silverstein, 2002).…”

Role of Toll Like Receptor 4 in Alzheimer’s Disease

“…TLRs recognizing bacterial and fungal components (TLR 1, 2, 4, 5, 6) are expressed on the cell surface, while sensors of viral and nucleic acids (TLR 3,7,8,9,10,11,12,and 13) are localized within endosomal compartments, where TLR4 can also be translocated (1,2). The association of TLRs with their specific ligands initiates intracellular signaling routes through the adaptor MyD88, except for TLR3 that signals via TRIF.…”

Synaptic Pruning by Microglia in Epilepsy

“…Furthermore, activation of microglial toll-like receptor 9 (TLR9) after epileptic seizures inhibits neurogenesis in kainic acid model mice [62]. Toll-like receptors (TLRs) activate innate immune responses through recognition of DNA and RNA derived from pathogens, and microglia express various types of TLRs in addition to TLR9 [63]. Thus, further studies on the roles of microglial TLRs in the epileptic brain should be conducted.…”