The dysregulation of innate immunity by Porphyromonas gingivalis in the etiology of Alzheimer's disease

The etiology of Alzheimer's disease (AD) remains under active debate. In this perspective, we explore the hypothesis that a primarily infection-caused chronic dysregulation and weakening of human innate immunity via the underexpression, degradation, and inactivation of innate immune proteins necessary for direct antimicrobial effects and regulation of host defense and autophagy could lead to AD. Key evidence relates to the fact that important innate immune proteins such as LL-37-which can bind Aβ and block amyloid formation-as well as Apolipoprotein E, antiviral interferons, and TNF-α can be degraded and deactivated by enzymes produced by the common oral anaerobic pathogen Porphyromonas gingivalis (Pg). Pg produces numerous virulence factors; of particular importance for AD are Pg's gingipain cysteine proteases. Deleterious effects of chronic Pg infection and gingipains include a systemic downregulation and paralysis of the interferon response, particularly the antiviral interferon-lambda response, which enables replication of endemic herpesviruses. The result is a chronic, low-level viral infectious assault on gut, nerves, and brain causing the production of Aβ antimicrobial peptides, accumulation of Aβ plaques, phosphorylation of Tau, progressive neuroinflammation, and neurodegeneration. The resultant innate immune system dysregulation, as an AD etiology, ties together the well-known amyloid cascade hypothesis and the infectious theory of AD into a unified explanation of the pathology and cause of AD. If this theory holds true, it suggests preventative approaches: (1) test for and eradicate Pg from oral flora, and/or directly deactivate the gingipains; and (2) reduce Herpesvirus exacerbations by the use of antiviral drugs and/or vaccines (e.g., Bacillus Calmette-Guérin).