Background
Alzheimer’s disease (AD), the leading cause of dementia, is projected to affect 152 million individuals worldwide by 2050; yet its pathogenesis remains poorly understood and effective treatments are lacking. Epidemiological studies consistently show that patients with chronic periodontitis have a significantly elevated risk of developing AD, and Porphyromonas gingivalis (P.g), a keystone periodontal pathogen, has been detected in the brains of AD patients--its presence being associated with a greater than 6-fold increase in AD risk. Although P.g infection has been demonstrated to induce AD-like pathologies in mice, including amyloid-β deposition, Tau hyperphosphorylation, and neuroinflammation, the precise molecular mechanisms by which it drives neuroinflammation remain a critical gap in the field. Given the central role of microglia, the resident immune cells of the central nervous system, in driving neuroinflammation, and the emerging involvement of ferroptosis, an iron‑dependent form of regulated cell death, in neurodegenerative diseases, this study focused on whether P.g hijacks the NOX4/PPAR‑α/PGC‑1α mitochondrial regulatory axis to induce microglial ferroptosis, thereby delineating the molecular pathway by which an oral pathogen remotely damages the brain.

Research Progress
This study, through in vivo and in vitro experiments, revealed the mechanism by which P.g induced microglial ferroptosis via the NOX4/PPAR-α/PGC-1α pathway, driving neuroinflammation and cognitive impairment. After 8 weeks of oral gavage with P.g, wild-type mice exhibited significant cognitive deficits (Fig. 1), hippocampal p-Tau deposition and neuroinflammation, along with abnormal expression of ferroptosis markers and mitochondria-related genes in the brain (Fig. 2). Knockdown of NOX4 in vitro restored PPAR-α/PGC-1α signaling, rescued mitochondrial function, and suppressed ferroptosis and the release of inflammatory cytokines (Fig. 3). Furthermore, Nox4 knockout mice resisted P.g-induced cognitive decline, neuronal damage, and neuroinflammatory responses (Fig. 4-5). This study revealed the complete molecular mechanism by which P.g induced microglial ferroptosis through the NOX4/PPAR-α/PGC-1α pathway, thereby driving neuroinflammation and cognitive impairment, providing a molecular target and theoretical basis for drug repurposing targeting NOX4 to intervene in periodontitis-associated Alzheimer's disease.

Future Prospects
This study provides multi‑level evidence demonstrating that P.g induces microglial ferroptosis through activation of the NOX4/PPAR‑α/PGC‑1α pathway, thereby driving neuroinflammation and cognitive impairment, and establishes NOX4 as a key molecular switch linking oral infection to AD-like brain pathology. Future research can be deepened in the following directions. First, current in vitro stimulation using P.g supernatant cannot yet determine the respective contributions of specific virulence factors such as gingipains, lipopolysaccharide, or outer membrane vesicles; precise resolution requires the use of purified proteins or gene-knockout bacterial strains. Second, P.g may also exacerbate AD pathology through indirect pathways such as the gut-brain axis; subsequent studies should employ germ-free animal models and assessments of intestinal barrier function to exclude or quantify the contribution of indirect routes. Third, there is an urgent need to validate the dynamic associations among brain NOX4 activity, peripheral ferroptosis biomarkers, and cognitive decline in large prospective clinical cohorts, and to advance research on brain-targeted delivery of NOX4 inhibitors in order to overcome the blood-brain barrier limitation, thereby truly achieving clinical translation from oral intervention to brain protection.

The complete study is accessible via DOI:10.34133/research.1163