Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders - PubMed

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Brain-resident macrophages (BRMs) include microglia and border-associated macrophages (BAMs), serving as immune sentinels in the CNS.
BRMs originate from embryonic yolk sac and fetal liver progenitors and self-renew throughout life.
Microglia maintain neural network homeostasis during neurodevelopment by phagocytosing apoptotic cells and pruning synapses.
In adulthood, microglia respond to infections, injuries, or protein aggregation, playing dual roles in repair and neurotoxicity.
BAMs, located in meninges, perivascular spaces, and choroid plexus, regulate boundary homeostasis and peripheral immune surveillance.
BRMs exhibit dual roles in neurodegenerative diseases (AD, PD, HD, MS) and brain injuries, both protecting and exacerbating damage.
In AD, microglia clear Aβ plaques via TREM2 and ADGRG1, while BAMs influence synaptic damage via CD36-ROS and SPP1 pathways.
In PD and HD, BRMs contribute to inflammatory responses linked to α-synuclein and mutant huntingtin.
In MS, BRMs modulate inflammation through antigen presentation and cytokine signaling.
Emerging therapies target BRMs, including NLRP3 inhibitors, TREM2 agonists, and interventions promoting neuroprotective microglial phenotypes.
Future strategies aim to reprogram BRMs from disease drivers to therapeutic allies in neurological disorders.

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