Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) 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 Aβ production and accumulation rather than merely accompanying amyloid deposition. In this review, we examine the molecular cross-talk between inflammatory signaling 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 γ-secretase through IFITM3, and activation of the C/EBPβ/δ-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 Aβ 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 signaling, 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.
Cipriano et al. (2026) studied this question.