Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology

Background Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether this response protects proteostasis or amplifies neuroinflammation remains unresolved. Microglia must engage, internalize and degrade pathological protein cargo, yet uptake alone may not indicate successful clearance. We investigated how loss of inducible immunoproteasome function affects AD-related protein pathology and microglial processing of pathological cargo. Methods We crossed L7M1 mice, which lack the immunoproteasome catalytic subunits β2i/MECL-1/PSMB10 and β5i/LMP7/PSMB8, with PS19 tauopathy mice and APP/human tau double-knock-in mice. Tau and amyloid pathology, glial reactivity, constitutive proteasome activity and behavior were evaluated in vivo. Microglial uptake and processing of tau aggregate-bearing material were examined using primary microglial cultures, live-cell imaging and longitudinal in vivo two-photon microscopy. Mouse single-nucleus RNA sequencing and reanalysis of two human single-nucleus transcriptomic datasets were used to define associated cellular programs. Isolated brain mitochondrial respiration was also assessed. Results Immunoproteasome deficiency increased phospho-tau burden and microglial reactivity in PS19 mice and exacerbated tau and amyloid-β pathology in APP/human tau double-knock-in mice. These pathological changes occurred without detectable suppression of constitutive 26S proteasome activity. Although immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material, live-cell imaging showed inefficient resolution of internalized cargo. Longitudinal two-photon imaging similarly demonstrated retention or accumulation of microglia-associated tau in immunoproteasome-deficient mice, identifying a post-engulfment degradative defect in vivo. Single-nucleus transcriptomics revealed a remodeled P2ry12low/Trem2high microglial state accompanied by altered phagolysosomal cargo-processing and mitochondrial programs. In two human datasets, lower microglial immunoproteasome expression was associated with cargo-processing gene-program changes that overlapped with those observed in immunoproteasome-deficient mouse microglia. Despite transcriptional suppression of mitochondrial programs, no detectable impairment of isolated brain mitochondrial respiration was observed. Conclusions These findings support immunoproteasome biogenesis as a protective glial stress response that facilitates post-engulfment processing of pathological cargo and restrains tau and amyloid accumulation in AD-relevant brain environments. They further distinguish microglial engagement and uptake from successful intracellular resolution, identifying immunoproteasome function as an important component of aggregate clearance in AD.