Alzheimer's Disease: A Molecular Model and Implied Path to Improved Therapy.

Amyloid-associated neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by the in-brain accumulation of ß-sheet structured protein aggregates called amyloids. However, neither a disease model nor therapy is established. We review past data and present new, preliminary data and opinions to help solve this problem. The following is the data-derived model/hypothesis. (1) Amyloid-forming proteins have innate immunity functions implemented by conversion to another sheet conformation, α-sheet. (2) In health, α-sheet structured, amyloid-forming proteins inactivate microbes by co-assembly with microbe α-sheets. Amyloid-forming proteins then undergo α-to-ß-sheet conversion. (3) In disease, α-sheet-structured, amyloid-forming proteins over-accumulate and are neuron-toxic. This hypothesis includes formation by virus capsid subunits of α-sheets. In support, we find that 5-10 mM methylene blue (MB) at 54 °C has a hyper-expanding, thinning effect on the phage T4 capsid, as seen by negative stain- and cryo-electron microscopy after initial detection by native gel electrophoresis (AGE). Given the reported mild anti-AD effect of MB, we propose the following corollary hypothesis. (1) Anti-AD MB activity is, at least in part, caused by MB-binding to amyloid α-sheet and (2) MB induces the transition to α-sheet of T4 capsid subunits. We propose using AGE of drug incubated T4 to test for improved anti-AD activity.

Extracellular Interaction of Bacillus thuringiensis, ATP and Phage 0105phi7-2: A Potential New Anti-Bacterial Strategy.

The following hypothesis proposes non-diffusive, environmental bacteriophage (phage) motion. (1) Some phage-hosting, motile bacteria undergo chemotaxis down ATP concentration gradients to escape lysis-inducing conditions, such as phage infection. (2) Some phages respond by non-infective binding to the motile bacteria. (3) When the bacteria reach a lower ATP concentration, which is a condition that signals increased density of phage-susceptible bacteria, the phage converts, Trojan-horse-like, to productive binding and infection. This hypothesis was previously proposed for Bacillus thuringiensis siphophage 0105phi7-2. It is tested here and confirmed with the following observations. (1) B. thuringiensis is found, macroscopically, preferentially located at low ATP concentrations when propagated in-gel after inoculation in the center of an artificially generated ATP concentration gradient. (2) Inoculating phage 0105phi7-2 at the bacteria inoculation site, 2-3 h after inoculation of bacteria, results in cell lysing activity that moves with the bacteria, without a visible trail of lysis. Trojan-horse-like behavior is consistent with only biofilm-inhabiting phages because environmental selection for this behavior requires limited fluid flows. We propose using artificial ATP concentration gradients to instigate Trojan-horse-like phage behavior during phage therapy of bacterial biofilms.