Neuroinflammatory suppression with protocatechuic acid attenuates Alzheimer's disease phenotypes in 5 ×FAD transgenic mice

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathobiology that includes neuroinflammation, the accumulation of extracellular amyloid-beta (Aβ) plaque, and intracellular neurofibrillary tangles comprising tau. Increasing evidence suggests that the aberrant activation of glial cells, including microglia and astrocytes, is a significant early characteristic that accelerates neuroinflammatory processes in the development of AD. Protocatechuic acid (PCA), a natural phenolic compound, has been investigated for its anti-inflammatory properties in various pathological conditions. Here, we demonstrated that administration of PCA significantly ameliorated neuroinflammation as well as cognitive deficits in the 5 ×FAD mouse model of AD, which overexpresses human amyloid precursor protein (APP) and presenilin-1 (PSEN1) genes carrying five familial Alzheimer's disease (FAD) mutations, leading to accelerated Aβ deposition. We further confirmed that PCA treatment significantly reduced microglial activation and downregulated the production of pro-inflammatory cytokines, astrogliosis, and tau hyperphosphorylation, thereby preserved the integrity of hippocampal neurons. Our RNA sequencing analysis revealed that PCA treatment restored the transcriptomic profile of hippocampal tissues in 5 ×FAD mice, particularly by downregulating genes associated with innate immune and inflammatory responses. Moreover, PCA alleviated gut dysbiosis and enhanced the integrity of the intestinal barrier. The findings suggest that PCA may serve as a promising therapeutic agent for early intervention in AD to mitigate its progression.