α1-Antit్రిpsin, Mikrogliyal NLRP3 İnflamazom Aktivasyonunu Kannabinoid Reseptör 2 Sinyal Yoluyla Azaltarak α-Sinükleinopati ile İlişkili Davranışsal Defisitleri İyileştirir

Özet (abstract)

Abstract α-Synucleinopathies are marked by persistent neuroinflammation and disabling non-motor symptoms involving nucleus accumbens (NAc) dysfunction, yet the neuroimmune mechanisms linking microglial activation to accumbal synaptic pathology remain poorly understood. Here, we identify α1-antitrypsin (AAT) as a previously unrecognized modulator of cannabinoid receptor 2 (CB2R)-associated signaling in α-syn pathology. An acute transcriptomic screen revealed prominent induction of the Serpina1 gene family, while primary-microglial and chronic AAV–α-syn experiments showed that Cnr2 deficiency amplified Serpina1 /AAT responses, consistent with an insufficient compensatory reaction to persistent inflammation. Molecular docking, reciprocal co-immunoprecipitation, and surface plasmon resonance provided complementary evidence supporting an AAT–CB2R association under the respective assay conditions. Functionally, AAT reduced the α-syn-associated elevation of intracellular cAMP in an AM630-sensitive manner and attenuated ATP-evoked Ca 2 ⁺ responses, calpain-1 activity, GSK-3β N-terminal cleavage, and NLRP3/caspase-1-related cytokine production; these effects were substantially diminished in Cnr2 -deficient microglia. Calpeptin reproduced key molecular effects, implicating calpain-related proteolysis in this neuroimmune response. In vivo, intracerebroventricular AAT preserved NAc synaptic ultrastructure, ameliorated excitatory synaptic abnormalities in dopamine D2 receptor-expressing medium spiny neurons, and improved fear-memory retrieval, spontaneous alternation, and anxiety-like behavior, without affecting novel object recognition or motor performance. Several effects were attenuated under Cnr2 -deficient conditions, although selected electrophysiological responses persisted. Our findings identify AAT–CB2R-linked signaling as a modulator of microglial inflammatory homeostasis and support the therapeutic potential of AAT for NLRP3-associated neuroinflammation and non-motor dysfunction in α-synucleinopathies.

Yazarların özeti; kaynağından alınmıştır. Molecular Biomedicine, 2026 · DOI ↗