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

Q: What role does P. gingivalis-LPS play in Alzheimer’s pathology?

P. gingivalis-LPS is linked to AD/ADRD by promoting amyloid-beta (Aβ) accumulation. In SH-SY5Y cells it activates amyloid precursor processes leading to increased Aβ1-42 and Aβ1-40 release.

Q: How do the experiments test the involvement of caspase-4?

The study uses caspase-4 knockdown with caspase-4–specific siRNA and pharmacologic inhibition with Ac-LEVD-CHO. Reversal of P. gingivalis-LPS effects supports a mediating role for caspase-4.

Q: Which Alzheimer’s pathway components are examined beyond caspase-4?

Presenilin-1 (PS1) is examined because it is a γ-secretase component essential for amyloidogenic APP processing and Aβ1-42 production. APP activation is also assessed.

Sep 29, 2026

Upload by Theodore

Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) is investigated as a driver of Alzheimer’s disease (AD) and related dementias (ADRD) by promoting amyloid-beta (Aβ) pathology. The work tests whether caspase-4, an inflammatory mediator that senses cytosolic LPS, mediates activation of an Alzheimer’s disease-associated amyloid secretase pathway. In SH-SY5Y cells, P. gingivalis-LPS increases APP and presenilin-1 (PS1) activity and elevates Aβ1-42 and Aβ1-40 release; these effects are reversed by caspase-4 knockdown or inhibition.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages1

Reading Time3 min

AccessFree to download

Background and hypothesis

Methods: caspase-4 knockdown and inhibition

Results: APP/PS1 activation and Aβ release

Implications for AD/ADRD pathogenesis

Innovation in Aging, 2025, Vol. 9, No. S2 651 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 andAβ in the pathogenesis of AD/ADRD. Abstract citation ID: igaf122.2224 P. GINGIVALIS-LPS ACTIVATES THE ALZHEIMER’S DISEASE-ASSOCIATED AMYLOID SECRETASE PATHWAY VIA CASPASE-4 Ambika Verma1, Gohar Azhar2, Pankaj Patyal1, Xiaomin Zhang1, and Jeanne Wei2, 1. University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States, 2. University of Arkansas for Medical Sciences, Little Rock, AR, LITTLE ROCK, Arkansas, United States 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 thecaspase-4 inhibitor Ac-LEVD-CHO. Presenilin-1 (PS1), a key γ-secretase component, is essential for amyloidogenic APP processing andAβ1-42 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

FAQs

What role does P. gingivalis-LPS play in Alzheimer’s pathology?

P. gingivalis-LPS is linked to AD/ADRD by promoting amyloid-beta (Aβ) accumulation. In SH-SY5Y cells it activates amyloid precursor processes leading to increased Aβ1-42 and Aβ1-40 release.

How do the experiments test the involvement of caspase-4?

The study uses caspase-4 knockdown with caspase-4–specific siRNA and pharmacologic inhibition with Ac-LEVD-CHO. Reversal of P. gingivalis-LPS effects supports a mediating role for caspase-4.

Which Alzheimer’s pathway components are examined beyond caspase-4?

Presenilin-1 (PS1) is examined because it is a γ-secretase component essential for amyloidogenic APP processing and Aβ1-42 production. APP activation is also assessed.

Sep 29, 2026

Upload by Theodore