Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis

Abstract

Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer's disease is necessary. Recent studies have revealed increasing evidence for the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-established roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines produced by microglia in Alzheimer's disease. A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation may play a key role in the pathogenesis of Alzheimer's disease. Here we review recent findings on the roles played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer's disease. In each case, landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases, the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium, in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer's disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of the pathogenic mechanisms underlying Alzheimer's disease, and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer's disease brain.

Keywords: Alzheimer’s disease; IGF-1; Trem2; adult neurogenesis; microglia; neuroinflammation.

Figure 1

Heterogeneity of microglial activation. Sentinel (M0) microglia are highly active surveyors of their microenvironment, and upon detecting pathogenicity, such as through exposure to lipopolysaccharide (LPS) or interferon-γ (IFN-γ), they attain an M1 phenotype by inducing a highly inflammatory transcription profile and secreting pro-inflammatory cytokines, cytotoxic reactive oxygen species (ROS) and nitric oxide (NO). Once the disease or injury has been deemed resolved, the presence of immunosuppressive interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) causes them to shift to the acquired deactivation M2 phenotype. The M2 phenotype can also be induced through alternative activation in the presence of IL-4 and IL-13, such as in the type 2 T helper cell secretory response. M2 microglia can be characterized by the secretion of anti-inflammatory cytokines and growth factors such as insulin-like growth factor 1 (IGF-1), in addition to their phagocytosis of extracellular debris. This plasticity of microglial phenotype forges a negative feedback loop wherein microglia can restrain the neuroinflammatory response within a critical window, below the threshold of self-toxicity, to allow rapid eradication of pathogenicity, whilst minimizing collateral damage to central nervous system parenchyma. TNF-α: Tumor necrosis factor-α.

Figure 2

Trem2 and microglial responses to Aβ. Trem2 has nanomolar affinity for oligomeric Aβ species and enhances microglial chemotaxis to plaques in mouse models. (A) Microglia with wild-type Trem2 contribute to proteostasis through micropinocytosis of soluble Aβ oligomers and phagocytosis of Aβ fibrils. Microglial clustering around plaques forms a dense boundary to prevent outward diffusion of toxic Aβ and plaque expansion. (B) Microglia with a loss-of-function Trem2 variant display less efficient Aβ-directed chemotaxis, phagocytosis and boundary formation programmes. The plaques are less compact and show high seeding activity, leading to enlarged Aβ protofibrillar hotspots, higher inclusion of dystrophic neurites and increased neuronal loss. Aβ: β-Amyloid; NFT: neurofibrillary tangle.

Figure 3

Promotion of neuronal survuval by microglia. Microglial expression of anti-inflammatory factors, such as IL-10, creates a milieu that is inductive of tissue repair and remodelling programmes. Microglial secretion of TGF-β can also induce astrocytes to undergo proliferative reactive gliosis to form a neuroprotective glial scar. Microglia promote neuronal survival through the secretion of neurotrophic factors, including IGF-1, and the elimination of axosomatic inhibitory synapses, thus upregulating neuron-endogenous synthesis of anti-apoptotic molecules such as Bcl-2 or Fgf2. Aβ: β-Amyloid; DCX: doublecortin; GFAP: glial fibrillary acidic protein; GN: granule neuron; IGF-1: insulin like growth factor-1; IL-10: interleukin 10; INP: intermediate neuronal progenitor; NFT: neurofibrillary tangle; QNP: quiescent neural progenitor; Sox2: sex determining region Y-box 2; TGF-β: transforming growth factor beta.

Figure 4

Modulation of adult neurogenesis by microglia. Microglial phagocytosis of cellular debris from apoptotic neural progenitors is an important homeostatic mechanism in the neurogenic niche. Type II INPs express Ki-67 and Nestin, whilst Type III INPs and immature GNs express DCX and polysialylated neural cell adhesion molecule (PSA-NCAM). Microglial secretion of TGF-β has a complex effect on neurogenesis, with one hallmark effect being to promote the differentiation of neural progenitors to PSA-NCAM positive cells. The transcriptomic profile of mature GNs is characterised by the expression of neuronal nuclear marker (NeuN), Prox-1, calbindin, and neuron-specific class III beta-tubulin (βIII-tubulin). Microglial secretion of trypsinogen augments the number of βIII-tubulin-positive cells, potentially through a mechanism functioning upstream in the neurogenic cascade. BLBP: Brain lipid binding protein; DCX: doublecortin; GFAP: glial fibrillary acid protein; GN: granule neurons; IGF-1: insulin like growth factor; INP: intermediate neuronal progenitor; QNP: quiescent neural progenitors; Sox2: sex determining region Y-box 2; TGF-β: transforming growth factor beta.