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Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology
Srikanth M, Jiang S, Wellman SM, Sarkar S, Lorman DE, Lantin T, Runyan AM, Kumar M et al.. bioRxiv, 2026-07-20
Topic: Inflammation, microglia and astrocytes
Immunoproteasome induction is prominent in Alzheimer’s disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-β pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate–bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12 low /Trem2 high microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.
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APA 7th
Srikanth, M., Jiang, S., Wellman, S. M., Sarkar, S., Lorman, D. E., Lantin, T., et al. (2026). Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology. bioRxiv. https://doi.org/10.64898/2026.07.14.738427
Vancouver
Srikanth M, Jiang S, Wellman SM, Sarkar S, Lorman DE, Lantin T, et al. Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology. bioRxiv. 2026. doi:10.64898/2026.07.14.738427.
BibTeX
@article{srikanth2026-e12d5e2b,
author = {Srikanth, M. and Jiang, S. and Wellman, S. M. and Sarkar, S. and Lorman, D. E. and Lantin, T. and Runyan, A. M. and Kumar, M. and others},
title = {{Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.07.14.738427},
url = {https://doi.org/10.64898/2026.07.14.738427}
}
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Key findings
- Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia.
- Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.
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Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 35 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 22 of the 62 points we could judge it on, which is 35 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 22 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 22 of the 62 points we could judge it on is 35 out of 100. |
| Total | 35 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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