Targeting Microglial Population Dynamics in Alzheimer's Disease: Are We Ready for a Potential Impact on Immune Function?

Abstract

Alzheimer's disease (AD) is the most common form of dementia, affecting two-thirds of people with dementia in the world. To date, no disease-modifying treatments are available to stop or delay the progression of AD. This chronic neurodegenerative disease is dominated by a strong innate immune response, whereby microglia plays a central role as the main resident macrophage of the brain. Recent genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) located in microglial genes and associated with a delayed onset of AD, highlighting the important role of these cells on the onset and/or progression of the disease. These findings have increased the interest in targeting microglia-associated neuroinflammation as a potentially disease-modifying therapeutic approach for AD. In this review we provide an overview on the contribution of microglia to the pathophysiology of AD, focusing on the main regulatory pathways controlling microglial population dynamics during the neuroinflammatory response, such as the colony-stimulating factor 1 receptor (CSF1R), its ligands (the colony-stimulating factor 1 and interleukin 34) and the transcription factor PU.1. We also discuss the current therapeutic strategies targeting proliferation to modulate microglia-associated neuroinflammation and their potential impact on peripheral immune cell populations in the short and long-term. Understanding the effects of immunomodulatory approaches on microglia and other immune cell types might be critical for developing specific, effective, and safe therapies for neurodegenerative diseases.

Keywords: Alzheimer’s disease; microglia; neurodegenerative diseases; neuroinflammation; proliferation.

Figure 1

CSF1R/CSF-1/IL-34-dependent tissue-resident macrophage key functions. CSF1R-, CSF1- and IL-34-dependent macrophage populations perform key functions to maintain homeostasis in different organs. Microglia, the main resident macrophages in the brain, is responsible for many critical functions during development and adulthood including support of neurogenesis, synaptic formation, and pruning, and phagocytosis of apoptotic neurons and debris in the extracellular space (Colonna and Butovsky, ; Li and Barres, 2018). In the lungs, alveolar macrophages are responsible of the clearance of inhaled pathogens and particles (Maus et al., ; Davies et al., 2013), and they also play a critical role in the maintenance of alveolar homeostasis by clearing lipoprotein-containing alveolar surfactant produced by alveolar epithelial cells (Dranoff et al., ; T’Jonck et al., 2018). Kupffer cells, the resident macrophages in the liver, are involved in many immune and homeostatic functions such as clearing gut-derived toxins and pathogens from the blood, removal of damaged erythrocytes, as well as iron, bilirubin, and cholesterol metabolism (Ganz, ; T’Jonck et al., 2018). The spleen contains multiple subsets of macrophages such as red pulp macrophages, located in the red pulp of the organ. They play a vital role in the clearance of senescent red blood cells and iron recycling (Kurotaki et al., ; T’Jonck et al., 2018). Next to red pulp macrophages, the spleen also contains marginal zone macrophages that are involved in the detection of antigens present in the bloodstream (den Haan and Kraal, ; Kierdorf et al., 2015). Adipose-associated macrophages, present in the pancreas and adipose tissue all over the body, fulfill different functions such as removal of dead adipocytes, regulation of adipocyte lipolysis, storage and release to the bloodstream of excessive adipocyte-released lipids, and participation in the control of insulin sensitivity (Odegaard et al., ; Boutens and Stienstra, ; T’Jonck et al., 2018). Macrophages in the gastrointestinal tract continuously interact with the intestinal microbiome and maintain intestinal homeostasis regulating the immune response to commensals and defending the tissue against pathogens (Davies et al., ; Zigmond and Jung, 2013). Langerhans cells are resident macrophages in the skin, involved in tissue surveillance, and uptake, and transport of antigens to the skin-draining lymph nodes (Chorro and Geissmann, ; Kierdorf et al., ; T’Jonck et al., 2018). Renal macrophages play several roles such as surveillance of the environment, phagocytosis of pathogens, and debris present in the extracellular matrix as well as support for nephrogenesis (Nelson et al., 2012). Circulating Ly-6C^lo monocytes are the predominant macrophage subset in the blood, acting as “intravascular housekeepers” in the clearance of endothelial cell debris as well as entering other tissues for the replenishment of tissue macrophage populations (Carlin et al., ; Gordon et al., 2014). Finally, different types of macrophages play critical roles in the bone. Osteoclasts are large multinucleated macrophages in charge of maintaining bone homeostasis and structure by resorption of the bone matrix produced by osteoblasts (Davies et al., ; T’Jonck et al., 2018), whereas bone marrow macrophages support erythropoiesis and maintain hematopoietic stem cells in stem cell niches (Chow et al., , ; Davies et al., 2013). Considering the shared myeloid lineage of all these macrophage populations, it is anticipated that the immune and homeostatic key functions above described are susceptible to be affected by the immunomodulatory strategies to reduce neuroinflammation.