Increasing prevalence of Alzheimer?s dementia (AD) is a growing health and economic crisis. Although studied for 112+ years, the root causes for sporadic AD?which is > 95% of AD?are unclear. Over the last 15 years, 415+ clinical trials to test new drugs against AD failed. Approved drugs can only manage symptoms. I will use NIH Pioneer funding to investigate a novel hypothesis for the etiology of sporadic Alzheimer?s dementia, based on my insight that imbalance between two innate immune peptides may be a key factor that modulates the risk of formation, the stability, and clearance of AD-associated fibrils and plaques. Recent observations of chronic P. gingivalis and Herpesvirus infections being associated with Alzheimer?s fit this hypothesis. I am, to my knowledge, the only researcher working on this idea. The human cathelicidin LL-37, unique in our proteome, is an antiviral and antibacterial defense peptide deployed by microglia, macrophages, neutrophils, epithelia, B cells, and NK cells (to kill infected cells). Thus LL-37 is a centrally important defense peptide, necessary for killing bacterial and viral pathogens and infected host cells. LL-37?s Vitamin D3-, RXR-agonist-, and butyrate-dependent expression is also stimulated by infection, wounding, exercise, and some vaccines (e.g., BCG & OPV vaccines). Certain pathogens, P. gingivalis in particular, release enzymatic virulence factors that rapidly degrade LL-37. Degradation of LL-37 could well dysregulate the brain?s innate immunity, causing neurodegeneration; in LL-37?s absence, the immune process of macroautophagy is crippled. The Alzheimer?s-associated peptide Ab now seems also to be a host defense peptide; brain infections by either Herpesviridae or P. gingivalis stimulate Ab production, causing it to accumulate in plaques that co-locate with pathogens. Recently I and collaborators showed that LL-37 and Ab are both expressed in human brain, and bind each other sequence-specifically. LL-37/Ab binding prevents fibrillization and blocks Ab from adopting b-type secondary structure. Thus, LL-37 degradation may allow Ab to accumulate. Our in vivo studies show that cathelicidin induction in 5XFAD mice slows AD progression and improves 5XFAD cognition to match wild-type.
I aim to tie this finding to infection-associated dementia. In this Pioneer project, I will use wild-type and cathelicidin KO mice to demonstrate that degradation of LL-37 by P. gingivalis virulence factors may well be one cause of brain tissue degradation leading to dementia, which can be prevented by early upregulation of cathelicidin to prevent infection; or treated orally with antimicrobials. My lab has developed new antimicrobials that potently kill both P. gingivalis and inactivate Herpesvirus.
The human cathelicidin peptide LL-37 is unique in our proteome, and is central to innate immunity as an antibacterial and antiviral defense molecule released from immune and epithelial cells. Based on Dr. Barron?s discovery that LL-37 binds the Alzheimer?s-associated peptide Ab, forming a stable nontoxic complex, halting Ab fibril formation, and abolishing Ab cytotoxicity to neurons, this project will determine whether chronic, oral P. gingivalis infection sets the stage for dementia via degradation of LL-37, and a subsequent crippling of the brain?s immune defense and regeneration mechanisms. In vivo studies will explore this novel innate immune etiology and mechanism for sporadic Alzheimer?s dementia, and test whether disease is prevented by early-life upregulation of LL-37 to disallow establishment of infections. !
