(194a) Invited: The Complex Natural Bionanotechnology of Autoimmune Disease, Atherosclerosis, and Plaque Diseases Including Alzheimer's and Parkinson's Disease

My lab developed and studied host defense peptide (HDP) mimics based on oligo-N-substituted glycines (peptoids). Peptoid HDP mimics were designed to emulate the cationic, helical HDPs (or “antimicrobial peptides”) such as magainin (frog) and LL-37 (human). We have examined mechanisms of action and selectivity (or lack of it) in many peptoid sequence variants, comparing with HDPs of interest. Here, selectivity is defined the propensity to incapacitate pathogens, with less (or, acceptable) levels of toxicity to host cells. For peptoid mimics as for HDPs, activity and selectivity depend upon net positive charge, hydrophobicity, amphipathicity, and self-association into meta-stable coiled coils that dissemble on binding to electronegative cell membranes. We undertook mechanistic studies with peptoid variants having high (or low) activity, and/or high (or low) selectivity, comparing to selective and non-selective HDPs. Vesicle leakage, membrane depolarization, and TEM yield surprising and we believe paradigm-shifting new information about HDP and HDP mimic mechanisms of killing.

       Unexpected insights into biology and physiology followed a realization that the most active antibiotic peptoids always carry concomitant cytotoxicity—as do HDPs, the human cathelicidin LL-37 in particular. I was struck in particular by similarities between antibacterial and cytotoxic activities of our HDP mimics and LL-37, a phylogenetically ancient innate immune effector that is unique in the human proteome and that plays indispensible, pleiotropic roles in vivo. Misregulated LL-37 is known, already, to play a role in the autoimmune diseases rosacea, eczema, psoriasis, and lupus erythematosus, and most likely also rheumatoid arthritis.

       In this lecture, I hypothesize a key role for LL-37 in the etiology of other human degenerative diseases, including Alzheimer’s and amyloid diseases including atherosclerosis, Type II diabetes, and other maladies, as consequences of LL-37’s intrinsic biophysical mechanisms of action, which can be both beneficial and damaging in a strongly concentration-dependent fashion. Dearth of LL-37 prevents normal autophagic cell maintenance, crippling cells over time. Yet disease can also result from overactivation of physiological triggers of LL-37's expression. Chronic nervous or traumatic hyperactivation of HDP expression, overstimulating the normally protective and beneficial HDP detoxification mechanisms, lead to hemolysis and trigger the deposition of atherosclerotic and amyloid plaque, which normally can be rapidly degraded by macrophages. However, frequent overexpression of LL-37 as a result of acute phase responses, occurring against a background of chronic underexpression and/or improper CAMP gene regulation (for instance as a result of inadequate Vitamin D3) can disrupt the balance between the two systems. Amyloid, initially formed around host cells to serve as "short-term" protective barrier that binds up endogenous cytotoxic HDPs preventing their disruption of essential cell processes, accumulates, engendering a "snowballing" of damaging, cytotoxic inflammatory processes.