Fibrils, Tangles, Plaques, Bugs and Plants
Last week an old colleague and friend from my academic days, kiwi expat and Stanford synchrotron guru Clyde Smith was in town and he suggested we catch up at the University of Auckland Public Lecture being given in conjunction with the annual meeting of the Asian Crystallographic Association (AsCA). The lecture was by one of the rock stars of structural biology, Professor David S. Eisenberg from UCLA, and the talk was “Proteins on the Edge: Amyloid Formation in Health and Disease”.
Having dabbled in structural biology once a long time ago in (I eventually managed to grow some crystals of my mutant lactoferrin and blasted them with a few X-rays back in the ‘90s), it was a YES from me! Also, a nice chance to see briefly see some people I’d worked with back in the day at the incredible Professor Ted Baker’s then, Massey University laboratory. But I digress. The chance to immerse my mind in what I view as an incredibly fascinating branch of science was too good to pass up.
Professor Eisenberg’s lecture was captivating. He transcribed what is incredibly deep science into a “salivating for more” story about the very nasty amyloid protein structures that occur in diseases such as Alzheimer’s and other dementias, motor neuron disease, some cancers and amyloidosis. These amyloid structures were identified back in 1906 by Alois Alzheimer as “plaques and tangles” but a lack of interest in this finding (when presented to the scientific community) was disappointing for Dr Alzheimer at the time, and meant that these structures remained largely unknown for around half a century.
Professor Eisenberg prefaced the science with a discussion of the economic impact of Alzheimer’s disease (only one of the diseases and conditions in which amyloid formation occurs). The figures are truly terrifying - in China the annual real GDP impact of Alzheimer’s disease is predicted to grow at an accelerating pace reaching US$1.07 trillion in 2050. The total cost of dementia to NZ is now around $1.7b and will reach around $5b by 2050. With the developed world’s ageing population, it’s not hard to see how this translates to other western countries and the magnitude of the global impact. Whilst the financial cost can be modelled and quantified, the personal burden of these diseases is tragic in its own right. We all know of someone who has suffered, or is suffering from these amyloid conditions, robbing them of their own humanity. Professor Eisenberg’s key takeout at this point was that we need drugs to treat this burgeoning issue that will have such a profound economic and social impact. Whilst I agree wholeheartedly that we do need drugs to hopefully prevent established disease progression and even treat these diseases to an improved patient outcome, my immediate thought was – what about preventative medicine and health? These diseases often take time to develop and with such an aetiology shouldn’t we be looking at how we could minimise the chance of these diseases taking hold in the first place?
Drug development for Alzheimer’s disease is riddled with problems and failures. Professor Eisenberg outlined that in the case of antibody therapy for amyloid disease, the scale of difference of the solution for the problem tells us the story of why. Delivering enough large antibodies into the brain to treat the numerous and much smaller amyloid structures, answers the question – you can’t get the drug to target ratio high enough – even if you could get it effectively into the brain tissue.
Professor Eisenberg took us through the captivating journey that is the story of the elucidation of the structural biology of amyloid fibrils. Understatement - it wasn’t easy and it turns out that these molecular structures are pretty unique. They form in tightly matted sheets 100,000s of layers thick and with interlocking sidearms and a line-up of hydrogen bonds that makes them both internally dry and incredibly strong. (I couldn’t help wondering if this new scientific knowledge will one day translate into industrial applications for incredibly strong proteinaceous materials outside of drug design – maybe it’s already underway).
Like all good scientific discoveries, a nice measure of accidental science occurred when a one of his team found his beaker full of protein formed a reversible gel (and what are the industrial applications of this). In a nutshell this work showed that it is possible to have a reversible amyloid fibril. Furthermore, it was shown that some of amyloid fibrils could occur due to cellular stress and were transient. It turns out that over 170 human proteins contain the amino acid sequence that can form these reversible amyloid fibrils. It’s when they become irreversible that the problems occur. Cellular stress and inflammation are understood to play a role.
Professor Eisenberg’s team is now visualising these molecules at atomic-level detail to design inhibitors that block fibril formation. Such inhibitors are typically peptides that bind to the top of a fibril and stop its growth and these are the targets for drug design. Some compounds are in animal trials already. Exciting stuff!
Lately I’ve been very interested in the growing body of literature (and consumer level buzz) about the microbiome. The 1014 microbial cells that comprise the human microbiome outnumber human host cells by approximately one hundred-to-one, the microbial genes of the microbiome outnumber human host genes by about one hundred-and-fifty to one, and together these microbes constitute the largest diffuse organ system in the body, more metabolically active than the liver.
The brain-gut axis and the implication of the microbiome on its function is also becoming increasingly understood. That is, there is a clear 2-way path between the brain and the gut that is physiologically important. Researchers have identified differences in the gut microbiome including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of Alzheimer’s disease patients. These findings add Alzheimer’s to the growing list of diseases associated with gut microbial dysbiosis, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.
It’s now been shown that inflammatory molecules produced by these gram negative gut bacteria such as Bacteroidetes can upset the balance of amyloid structure production and clearance, resulting in accumulation of amyloid structures in the central nervous system which can lead to Alzheimer’s and other diseases. This is known as the “amyloid cascade hypothesis of Alzheimer’s disease”
Recent work has also shown that some gut bacteria are necessary for the metabolism and absorption of the plant-derived micronutrients, polyphenols. One group working with polyphenols from grapes found polyphenol metabolites that were present in the brain in mice were primarily responsible for inhibiting the onset and progression of Alzheimer disease type pathophysiology. The compounds exerted their neuroprotective effects by interfering with the generation of neurotoxic amyloid structures.
There’s a buzz in this space with multiple articles and studies at different levels of science popping up on sites like Nutraingredients for acai, green tea, red wine, red cabbage, beetroot, cocoa, pomegranate and more. Purists will criticize some of these articles no doubt for their links to industry, and in some cases study quality. Here in New Zealand our unique "terrior" including our abundance of UV radiation gives our plants, fruits and vegetables very high polyphenolic compound concentration. Is this a competitive advantage we could capitalize on?
Where does this leave us? With plenty more questions than answers and opportunities for innovation.
The chance to hear one of the world’s leaders in the field of structural biology discuss his quest for answers about devastating amyloid disease, gave me some understanding about amyloid disease and encouraged me to take a look around and to question my knowledge of related science. What did I find? A whole bunch of interesting things. Correlation is not causation as we know, however the possible linkages of Professor Eisenberg’s work on amyloid structures, the microbiome and plant-based nutrition might be worth a closer look.
If nothing else it’s given my Gray matter a good work out.
Cover image credit: Prof Eisenberg