P. gingivalis-LPS Activates the Alzheimer’s Disease-Associated Amyloid Secretase Pathway via Caspase-4

TL;DR

This study shows that a harmful component from a gum disease bacterium activates Alzheimer's-related proteins, contributing to amyloid buildup linked to dementia.

Contribution

The study identifies caspase-4 as a novel mediator linking P. gingivalis-LPS to Alzheimer's amyloid pathology.

Findings

P. gingivalis-LPS activates APP and PS1, leading to increased Aβ production in SH-SY5Y cells.

Caspase-4 silencing or inhibition reduces LPS-induced Aβ peptide release.

Caspase-4 mediates neuroinflammation and amyloid pathology in AD/ADRD.

Abstract

Porphyromonas gingivalis, a periodontal pathogen, has been implicated in the pathogenesis of Alzheimer’s disease (AD) and related dementias (ADRD) through its virulent lipopolysaccharide (LPS) component. Amyloid pathologies, characterized by the accumulation of amyloid-beta (Aβ), are central features of AD/ADRD. Our previous work demonstrated that P. gingivalis-LPS treatment activated the amyloid precursor protein (APP) and leading to the production of Aβ1-42 and Aβ1-40 peptides in SH-SY5Y cells. Caspase-4, an inflammatory mediator that directly senses and binds to cytosolic LPS, plays a critical role in inflammatory signaling. However, the involvement of caspase-4 in P. gingivalis-LPS induced amyloid pathologies remains underexplored. We hypothesized that P. gingivalis-LPS contributes to AD/ADRD pathogenesis by activating the Alzheimer’s disease-associated amyloid secretase pathway mediated by caspase-4. To investigate this, we performed caspase-4 knockdown in SH-SY5Y cells using caspase-4 specific siRNA and the caspase-4 inhibitor Ac-LEVD-CHO. Presenilin-1 (PS1), a key γ-secretase component, is essential for amyloidogenic APP processing and Aβ1-42 production, was also examined. Our findings demonstrated that P. gingivalis-LPS treatment activated both APP and PS1 in SH-SY5Y cells, with caspase-4 silencing significantly reducing the expression of these proteins compared to negative control siRNA (p < 0.05). Furthermore, P. gingivalis-LPS induced elevated Aβ1-42 and Aβ1-40 peptide release was reversed upon treatment with caspase-4 siRNA or Ac-LEVD-CHO (p < 0.05). These results provide compelling evidence that caspase-4 mediates P. gingivalis-LPS induced neuroinflammation and highlight the complex interactions between caspase-4, APP, PS1 and Aβ in the pathogenesis of AD/ADRD.