Brain border-associated macrophages: common denominators in infection, aging, and Alzheimer's disease?

Abstract

Mammalian brain border-associated macrophages (BAMs) are strategically positioned to support vital properties and processes: for example, the composition of the brain's perivascular extracellular matrix and cerebrospinal fluid flow via the glymphatic pathway. BAMs also effectively restrict the spread of infectious microbes into the brain. However, while fighting infections, BAMs sustain long-term transcriptomic changes and can be replaced by inflammatory monocytes, potentially leading to a gradual loss of their beneficial homeostatic functions. We hypothesize that by expediting the deterioration of BAMs, multiple infection episodes might be associated with accelerated brain aging and the putative development of neurodegenerative diseases. Our viewpoint is supported by recent studies suggesting that rejuvenating aged BAMs, and counterbalancing their detrimental inflammatory signatures during infections, might hold promise in treating aging-related neurological disorders, including Alzheimer's disease (AD).

Figure 1.. Schematic view of BAMs and their presumed roles before, during, and after different infections in mice.

The three boxes represent border regions of the brain (e.g., dural meninges) at 3 timepoints (before, during, after infection). At steady-state (left box), BAMs are polarized through IL-4 and maintain brain function [32,34]. A positive impact on the brain is noted by the “red cross” sign. In an infectious context (middle box), BAMs play a key role in fighting pathogens and protecting the brain [–16,36]. Red lines represent the defense provided by BAMs in each infectious context: upon S. agalactiae infection, BAMs reduce bacterial load but this is dampened by pain signals coming from CGRP⁺ nociceptors activated by the bacteria; upon LCMV acute neurotropic infection, BAMs strongly reduce viral load and require IFN-I for their activation; upon T. brucei infection, BAMs reduce parasite load but cannot block its dissemination into the brain. A thicker red line represents a stronger BAM defense role. After pathogen clearance (right box), inflamed BAMs maintain long-lasting transcriptomic and phenotypic alterations [16]. In addition, monocytes engrafting the meninges may affect brain function in the long run [26]. Monocytes can arrive via blood or hypothetically via the skull bone marrow (indicated as a question mark). Impact of post-infectious BAMs on brain function is still uncertain and indicated as a question mark. BAMs, border-associated macrophages; CGRP, calcitonin gene-related peptide; IFN-I, interferon type I; IL-4, interleukin-4; LCMV, lymphocytic choriomeningitis virus; S. agalactiae, Streptococcus agalactiae; SBM, skull bone marrow; T. brucei, Trypanosoma brucei. Figure created with Biorender.com.

Figure 2.. Scheme depicting the molecular signatures of parenchymal microglia and recruited monocyte-derived macrophages in the vicinity of amyloid plaques in AD transgenic mice.

One of the main brain pathological hallmarks of AD is the extracellular deposition of amyloid plaques (rich in aggregated Aβ species), a feature that is mimicked in AD transgenic mice [48]. Aging and the development of brain Aβ pathology are linked to the appearance of DAM that encircle plaques and the blood monocyte-derived DIMs that secrete TNF [–60,63,64,74]. The possible contribution of skull bone marrow-derived myeloid progenitors to brain BAMs and DIMs in AD warrants further investigation. Green arrow represents a potentially protective mechanism. Red arrow represents a potentially deleterious mechanism. Dashed arrow with a question mark represents an unexplored connection. Aβ, amyloid beta; APOE, apolipoprotein E; CD83, cluster of differentiation 83; DAM, disease-associated microglia; DIMs, disease inflammatory macrophages; SBM, skull bone marrow; TNF, tumor necrosis factor; TREM2, triggering receptor expressed on myeloid cells 2. Figure created with Biorender.com.

Figure 3.. Glymphatic function and microglial activation are modulated by brain BAMs in mice.

Exacerbation of brain Aβ pathology with age in transgenic mice is linked to an altered BAM activation signature, with less LYVE-1 and more MHC-II expression at the surface [20,34]. Activated leptomeningeal BAMs alter the perivascular extracellular matrix leading to defective CSF/interstitial fluid (ISF) flow via the glymphatic system. Therapeutic delivery of CSF-1 into the murine brain rejuvenates BAMs, which upregulates LYVE-1, and leads to improved CSF glymphatic flow [34]. Activated BAMs, particularly PVMs, secrete osteopontin, which further exacerbates microglial activation and excessive neuronal synaptic pruning [77]. Green arrow represents a potentially protective mechanism. Red arrow represents a potentially deleterious mechanism. Aβ, amyloid beta; BAMs, border-associated macrophages; CSF, cerebrospinal fluid; CSF-1, colony stimulating factor-1; ISF, interstitial fluid; LYVE-1, lymphatic vessel endothelial hyaluronan receptor-1; MHC-II, major histocompatibility complex type-II; NVU, neurovascular unit. Figure created with Biorender.com.

Figure 4.. Scheme depicting newly described roles of brain innate immune cells in tau-mediated neurodegeneration.

The formation of intracellular neurofibrillary tangles and extracellular hyperphosphorylated tau aggregates is one of the brain pathological hallmarks of secondary tauopathies such as AD [48]. In mouse models of AD-like tauopathy expressing human APOE4, namely the PS19:APOE4 mice, increased microglial expression of MHC-II has been associated with increased recruitment of neurodegeneration-promoting activated T cell clones [78,79,84]. Yet, little is known about the contribution of MHC-II^high BAMs to this phenomenon. Red arrow represents a potentially deleterious mechanism. Dashed arrow with a question mark represents an unexplored connection. APOE4, human apolipoprotein E4 gene; BAMs, border-associated macrophages; MHC-II, major histocompatibility complex type-II; p-tau, hyperphosphorylated tau. Figure created with Biorender.com.