A Systems-Level Hypothesis for How Innate Immune System Dysregulation May Cause Alzheimer’s Dementia, and How We May be Able to Prevent It

We are investigating the early-stage etiology of sporadic Alzheimer's Dementia (AD), for which 420+ clinical trials by Pharma have failed over the past 15 years to produce any effective drug. What causes the accumulation of Aβ peptide-rich fibrils and plaques in an aging brain? What is Aβ's physiological function? We focus on Aβ's interactions with the human cathelicidin peptide, LL-37, an antibacterial and antiviral innate immune system effector and modulator that is ubiquitous in human tissues and expressed by myriad cell types, yet unique in the human proteome. Recently, evidence has built that chronic Herpesvirus or P. gingivalis infections of human brain tissue may precipitate many cases of sporadic dementia labeled as Alzheimer’s Disease. We present experimental evidence and discuss our developing hypothesis that the antiviral and antibacterial peptide LL-37, which can be chronically underexpressed in humans based on dietary and lifestyle factors or degraded by P. gingivalis virulence factors, is a natural binding partner of Aβ that inhibits formation of AD fibrils and plaques, such that LL-37 and Aβ have a toxin/antitoxin relationship. We demonstrate sequence-specific binding between LL-37 and Aβ by Transmission Electron Microscopy (TEM), Surface Plasmon Resonance Imaging (SPRi), circular dichroism (CD) spectroscopy, analytical ultracentrifugation (AUC) and Small-Angle X-Ray Scattering (SAXS). TEM shows that LL-37 inhibits the fibrillization of Aβ, especially the formation of long, straight fibrils characteristic of AD, while CD spectroscopy reveals that LL-37 binding prevents Aβ from adopting β-type secondary structure. AUC and SAXS show that LL-37 and Aβ form a unique, monodisperse, 1:1 molecular complex. Cell culture studies with primary human microglia and neuronal cells indicates that these two peptides, once they bind and form a complex, then neutralize each other’s effects on the cells. Finally, studies in 5XFAD and wildtype transgenic mice, as well as the fruit fly Drosophila Melanogaster, support these findings. We discuss what all of this means in the context of the prevention and treatment of Alzheimer’s dementia, and suggest several approaches that could be taken, in light of these results, to efficiently prevent (and possibly treat) AD.