{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:07:58Z","timestamp":1780402078743,"version":"3.54.1"},"reference-count":163,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","award":["RRC-2026-23688274"],"award-info":[{"award-number":["RRC-2026-23688274"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-\u03b2 (A\u03b2) plaque deposition, neurofibrillary tau tangles, synaptic dysfunction, and progressive cognitive decline. AD is increasingly recognized as a condition in which chronic neuroinflammation actively shifts amyloid precursor protein (APP) processing toward the amyloidogenic pathway, driving A\u03b2 production and accumulation rather than merely accompanying amyloid deposition. In this review, we examine the molecular cross-talk between inflammatory signalling and secretase regulation, highlighting how pro-inflammatory mediators promote amyloidogenic processing and contribute to downstream synaptic dysfunction. We discuss the major pathways linking glial activation to aberrant APP cleavage, including STAT3-dependent BACE1 upregulation, immune-mediated modulation of \u03b3-secretase through IFITM3, and activation of the C\/EBP\u03b2\/\u03b4-secretase axis, which connects inflammatory stress to both amyloid and tau pathology. We further address the contribution of epigenetic mechanisms, particularly microRNA-mediated derepression of BACE1 and suppression of ADAM10, as well as SIRT3-related impairment of A\u03b2 clearance. These interconnected processes establish a feed-forward pathogenic network in which neuroinflammation amplifies secretase imbalance, amyloidogenesis, and synaptic vulnerability. Finally, we discuss emerging multi-target therapeutic strategies aimed at modulating inflammatory signalling, restoring non-amyloidogenic APP processing, and preserving proteostatic and synaptic resilience. Collectively, this framework supports the view that targeting the inflammatory control of secretase activity may represent a biologically relevant strategy for disease modification in AD.<\/jats:p>","DOI":"10.3390\/ijms27114824","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:31:56Z","timestamp":1779885116000},"page":"4824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroinflammation and Secretase Regulation in Alzheimer\u2019s Disease: From Molecular Cross-Talk to Multi-Target Therapeutics"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-1455","authenticated-orcid":false,"given":"Giovanni Luca","family":"Cipriano","sequence":"first","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0215-2174","authenticated-orcid":false,"given":"Ivan","family":"Anchesi","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-0286","authenticated-orcid":false,"given":"Ivana","family":"Raffaele","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7882-2432","authenticated-orcid":false,"given":"Maria Francesca","family":"Astorino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4112-5542","authenticated-orcid":false,"given":"Aurelio","family":"Minuti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi \u201cBonino-Pulejo\u201d, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-9855","authenticated-orcid":false,"given":"Marco","family":"Calabr\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9703-0083","authenticated-orcid":false,"given":"Concetta","family":"Crisafulli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morpho-Functional Imaging\u2014BIOMORF, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102481","DOI":"10.1016\/j.arr.2024.102481","article-title":"Pathogenesis, Diagnostics, and Therapeutics for Alzheimer\u2019s Disease: Breaking the Memory Barrier","volume":"101","author":"Kamatham","year":"2024","journal-title":"Ageing Res. 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