Balancing Microglial Density and Activation in Central Nervous System Development and Disease

Abstract

Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.

Keywords: lifestyle modifications; microglia; neurogenesis; neurological diseases; synaptic pruning; therapeutic interventions.

Figure 1

Microglial Regulation on Neurogenesis. (A) Microglia regulates neurogenesis in ventricular–subventricular zone (V-SVZ); (B) perinatal stress induces neuroinflammatory programming, increase in microglial density, and disrupted synaptic refinement of neuron; (C) stress-induced epigenetic changes and neuroinflammation of microglia; (D) microglial miR124 and neurogenesis; (E) modulation of NPC-microglia crosstalk in NPC transplantation, microglial metabolism from pro-inflammatory glycolysis (M1) to OXPHOS-dominated anti-inflammatory state (M2). (Arrow: activation; red blunt arrow: inhibition; red thick arrow in panel (B): increase).

Figure 2

Synaptic pruning in neural circuit optimization. (A) Tag-and-eliminate strategy: microglia employ a “tag-and-eliminate” strategy in which complement cascade components (C1q/C3b/CR3) label weak synapses for phagocytic removal. (B) Neuronal CX3CL1 binds microglial CX3CR1, triggering dendritic spine engulfment via MFGE8 release. (C) Microglial phagocytic function is regulated by CSF1R homeostasis, a receptor system sustained by CSF1 and IL34; PLX5622 inhibits function of CSF1R. (D) Other molecular machinery of synaptic pruning. TREM2-DAP12 regulates microglial synaptic surveillance, and TREM2-β-catenin mediates survival; TGFβR2, MECP2 and IKZF1 involve microglial phagocytic function. (E) Synaptic stabilization and pathological engulfment through context-dependent molecular mechanisms. (Arrow: activation; red blunt arrow: inhibition; dot-headed arrow: receptor on the membrane).

Figure 3

Phase-dependent microglial dysregulation in Alzheimer’s disease (AD). (A) Early protective phase and late degenerative phase. (B) Microglial response to Aβ plaques and tau-microglia crosstalk; (C) Therapeutic implications targeting microglia in AD. (Arrow: activation; Red blunt arrow: inhibition; Dot-headed arrow: receptor on the membrane; red thick arrow in panel (C): increase; green thick arrow in panel (C): decrease).

Figure 4

Microglial orchestrators of α-synucleinopathy in Parkinson’s disease (PD). (A) Phage-dependent microglial activation in PD pathogenesis. Early protective phase and late chronic phase. (B) Therapeutic implications and modulation targeting microglial checkpoints in PD. (Arrow: activation; red blunt arrow: inhibition; dot-headed arrow: receptor on the membrane; red thick arrow: increase; green thick arrow: decrease).

Figure 5

Microglial dysregulation in mutant Huntingtin proteostasis. (A) Microglial and neuronal change in Huntington’s disease (HD) (Left panel) and mTTT subversion of microglial homeostasis in HD. (B) Therapeutic rebalancing of microglial state in HD, including NPC transplantation (Left panel) and pharmacological interventions (Right panel). (Arrow: activation; red blunt arrow: inhibition).

Figure 6

Spinal microglial dichotomy in amyotrophic lateral sclerosis (ALS). (A) Microglial biphasic response in ALS, from early neuroprotective (Left panel) to late-stage neurotoxicity (Right panel). (B) Phase-locked microglial reprogramming in SOD1 pathogenesis. (C) Therapeutic mechanism and regional targeting basing on spinal microglia resistant to CSF1R inhibition. (Arrow: activation; red blunt arrow: inhibition; red thick arrow: increase; green thick arrow: decrease).

Figure 7

Therapeutic innervation targeting microglia. (A) Microglial CSF1R and microglial survival. (B) ATP receptor modulation. (C) Pharmacological modulation in different diseases. (Dot-headed arrow: receptor on the membrane; arrow: activation; red blunt arrow: inhibition; red thick arrow: increase; green thick arrow: decrease; LPS, lipopolysaccharide; ROS, reactive oxygen species; HAB, high-anxiety behavior; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; CNS, central nervous system).

Figure 8

Lifestyle modification effect on microglia. (A) Polyunsaturated Fatty Acids exhibit anti-inflammatory and neuropeptide in the CNS. (B) Environmental toxins induce inflammatory and apoptosis of microglia. (C) Microbiome depletion changes microglial homeostatic state, reducing inflammation without severe side effects. (D) Environmental enrichment and exercise promote microglial proliferation and neurogenesis. (Arrow: activation; red cross mark: depletion or elimination).