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Emerging evidence identifies the immunoproteasome (iP), particularly the \u03b25i\/LMP7 subunit, as a central regulator linking these pathological processes. Unlike the constitutive proteasome, the iP is markedly induced in microglia, neurons, and astrocytes under inflammatory conditions through interferon-\u03b3 and NF-\u03baB signaling. This review discusses the dual and context-dependent role of the iP in AD pathogenesis. In microglia, chronic iP activation promotes degradation of NRF2, leading to oxidative stress, NLRP3 inflammasome activation, and the development of a senescence-associated secretory phenotype that exacerbates neuroinflammation and tau propagation. In neurons, moderate iP activity facilitates the clearance of phosphorylated tau; however, sustained overactivation generates aggregation-prone tau fragments that enhance trans-synaptic tau spreading. We further highlight the cross-talk between the iP and autophagy pathways through TFEB and p62\/SQSTM1 signaling and discuss how gut microbiota-derived inflammatory mediators may prime central iP activation through the gut\u2013brain axis. Importantly, recent preclinical studies support the concept of partial immunoproteasome modulation rather than complete inhibition, with selective LMP7 targeting restoring proteostatic balance, reducing microglial senescence, and attenuating tau pathology. Collectively, the iP emerges as a promising immunopharmacological target and a potential therapeutic rheostat in AD.<\/jats:p>","DOI":"10.1007\/s10787-026-02393-1","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:13:20Z","timestamp":1791000800000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The immunoproteasome in Alzheimer\u2019s disease: a dual regulator of tau pathology and microglial senescence"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5221-4666","authenticated-orcid":false,"given":"Mustafa M.","family":"Shokr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Abdelaziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"2393_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-025-03360-3","author":"C Acioglu","year":"2025","unstructured":"Acioglu C, Elkabes S (2025) Innate immune sensors and regulators at the blood brain barrier: focus on toll-like receptors and inflammasomes as mediators of neuro-immune crosstalk and inflammation. 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