Microglia in ALS: Insights into Mechanisms and Therapeutic Potential

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.

Keywords: ALS; microglia; neuroinflammation.

Figure 1

Roles of DAM in ALS: neuroprotective and neurotoxic. Under homeostatic conditions (yellow, center), microglia support neuronal health by clearing protein aggregates, releasing neurotrophic and anti-inflammatory factors, and providing immune surveillance. In ALS, however, these cells increasingly assume DAM phenotypes that can be both protective and harmful (right panel). On one hand, DAM help remove toxic aggregates and maintain synaptic integrity; on the other, they can release superoxide radicals and pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and secrete factors that convert astrocytes to a neurotoxic reactive state. This triggers excessive synaptic pruning, inflames tissue, and accelerates motor neuron loss. Thus, the dynamic balance between DAM-mediated neuroprotection and neurotoxicity is pivotal in determining ALS progression. This Figure was created with biorender.com.

Figure 2

DAM activation mechanisms. In the DAM model, microglia transition from homeostatic to stage 1 (Trem2-independent) and stage 2 (Trem2-dependent), each one with their own molecular and transcriptional signature. Arrows indicate genes that are up- or downregulated at each stage [25].