STAGE-DEPENDENT MODULATION OF ALS PROGRESSION BY PERIVASCULAR MACROPHAGES AT THE NEUROVASCULAR INTERFACE

Perivascular macrophages (PVMs) are CNS-resident myeloid cells located at the neurovascular interface and characterized by CD206 expression. Although PVMs contribute to blood–brain barrier homeostasis under physiological conditions, their role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the stage-dependent contribution of PVMs to ALS pathogenesis using the SOD1^G93A rat model.
PVMs were selectively depleted via intra-cisternal injections of clodronate-loaded liposomes, with PBS-loaded liposomes used as controls. Animals were assigned to four intervention paradigms: early presymptomatic, late peri-symptomatic, or repeated depletion initiated at either the presymptomatic or peri-symptomatic stage. Disease onset and progression were monitored longitudinally through body-weight measurements and locomotor behavioral assessments. Neuroinflammatory changes were evaluated using immunofluorescence at mid-stage and humane endpoints.
We observed accumulation of CD206⁺ PVMs across multiple CNS regions in end-stage SOD1^G93A rats, indicating their involvement in ALS-associated neuroinflammation. Clodronate treatment efficiently reduced PVM density for up to two weeks following injection. PVM depletion delayed disease onset across all intervention paradigms, with the most robust effect observed following repeated depletions that also increased survival. Behavioral analyses demonstrated a delayed symptomatic phase in repeatedly treated animals. Endpoint analyses revealed increased activation of PVMs, astrocytes, and microglia in the ventral horn of the spinal cord in depleted animals, suggesting a stage-dependent immunoregulatory role for PVMs.
These findings identify PVMs as dynamic modulators of ALS progression whose impact critically depends on the timing and persistence of intervention, highlighting the neurovascular immune niche as a promising therapeutic target in ALS.