Inflammation-associated serum amyloid A amplifies amyloid-β-driven oxidative stress and microglial activation

Systemic inflammation is increasingly recognised as a key modifier of Alzheimer’s disease (AD) progression, yet the mechanisms linking inflammatory acute-phase responses to Amyloid-β (Aβ)-driven neurotoxicity remain incompletely defined. Here, we report that amyloidogenic acute-phase peptide fragment SAA19–45 (SAA27), derived from Serum Amyloid A (SAA), modulates Aβ aggregation and amplifies downstream oxidative and inflammatory stress responses in neuronal and microglial systems. Immunofluorescence analysis of human AD brain tissue revealed plaque-associated SAA-positive cellular structures within or adjacent to Aβ-positive pathological microenvironments across all range of Braak stages. In vitro, co-incubation of SAA27 with Aβ accelerated Thioflavin T-positive aggregation kinetics and altered fibrillar organisation. In SH-SY5Y neurons, Aβ induced marked cytotoxicity and oxidative stress, and SAA27 selectively enhanced intracellular reactive oxygen species without a proportional increase in cell death. In HMC3 microglia, Aβ triggered oxidative stress and inflammatory activation, both of which were further amplified by SAA27, as reflected by increased reactive oxygen species and elevated IL-6 secretion. Similarly, SAA27 enhanced Aβ-induced IL-1β release in monocyte-derived microglia-like cells. In zebrafish larvae, Aβ and SAA27 co-injection produced a stronger ThT-positive amyloid signal and synaptic degeneration, compared with Aβ alone, supporting enhanced amyloid accumulation and synaptic disruption in vivo. Quantitative proteomics revealed Aβ-driven stress and proteostasis-related reprogramming in both neurons and microglia, with SAA27 biasing these responses toward oxidative and activation-associated pathways consistent with microglial remodelling and immune engagement. The polyphenol epigallocatechin gallate (EGCG) suppressed fibrillar aggregation in vitro and in zebrafish larvae, preserved synaptic integrity in vivo, attenuated oxidative and inflammatory responses, and differentially modulated cellular proteomic states, promoting near-restoration in neurons while inducing a distinct, less stress-associated state in microglia. Together, these findings identify SAA27 as an inflammation-associated co-factor that accelerates Aβ assembly and amplifies oxidative and innate immune stress responses. The observed partial overlap with human AD proteomic signatures further supports the disease relevance of these pathways. This work provides mechanistic insight into how systemic inflammatory states may exacerbate amyloid-driven neuroinflammation in AD and highlights inflammation-amyloid crosstalk as a pharmacologically modifiable axis.