Alzheimer’s disease (AD) affects over 40 million people worldwide: a number that is expected to grow to over 100 million by 2050.1 Despite this, there is a shortage of AD drugs on the market, with only five having been FDA approved, and no new ones since 2003.2 A major problem is that these drugs are merely symptomatic treatments. No drugs exist that stop or prevent AD. One of the hallmarks of AD are intracellular deposits of insoluble neurofibrillary tangles (NFTs) in neurons of the brain.3 NFTs are composed of aggregates of the microtubule-associated protein, tau. This study focuses on discovering novel treatments that prevent the aggregation of tau.

Peanut skins contain large amounts of procyanidins4: molecules proposed to have various health benefits.5 Peanut skin extract was run through high performance liquid chromatography (HPLC) to separate the many compounds present, in order to isolate procyanidin molecules. One particular procyanidin was separated and used for inhibition assays with tau and appeared to inhibit its aggregation into NFTs. It was then identified using electrospray ionization mass spectrometry (ESI-MS) and proton nuclear magnetic resonance (1H-NMR) to be the A1 procyanidin dimer isomer.

While running HPLC to isolate more procyanidin A1 for further experimentation, it became apparent that one of the pumps had a leak. This caused a lower percentage of that pump’s solvent to go through the column than what it was set to. This resulted in the presumably pure procyanidin A1 eluting later than usual, and separating from another, currently unidentified, molecule. Further experimentation led to the conclusion that the A1 procyanidin has no effect on the aggregation of tau, which was backed up by tests that were then done with a commercially available procyanidin A1 that was purchased. It is assumed that an unidentified contaminant is responsible for the inhibitory activity. Further studies are required to find which compound is responsible for the inhibition seen on tau aggregation.

One of the hallmarks of Alzheimer’s disease is pathological tau aggregation. We previously reported that cinnamaldehyde, found in cinnamon, could inhibit tau aggregation in vitro, by reacting with one or both of the two cysteines in tau. In my thesis, I use spectrophotometric methods to show that both cysteines display hyperreactivity over model sulfhydryl compounds by as much as four fold. The hyperreactivity is specific to cysteines in tau as opposed to those in other sulfhydryl-containing cellular proteins. Cinnamaldehyde (CA) displays several characteristics that make it favorable as a possible inhibitor of aggregation in vivo: it is a water-soluble, brain-permeable molecule that is non-toxic and inexpensive. I now show in my thesis that the hyperreactivity of CA toward tau specifically, as described in this thesis, is an additional favorable property towards the goal of being a potential therapeutic.