Turning Over a New Leaf
Surprising findings cast doubt on amyloid beta’s bad reputation in Alzheimer’s
Over the years, the search for Alzheimer’s therapies has targeted amyloid β – the accumulation of which is thought to perpetuate the neurological disease. But new research may cast the protein in an entirely different role: defender of the brain. A recent paper shows that amyloid β fights against microbial infections in the brains of animal models (1). We spoke with Robert Moir, co-lead researcher and Assistant Professor in Neurology at Harvard Medical School, to explore the implications.
Why study amyloid β’s role outside of Alzheimer’s disease?
It was prompted by a chance observation of remarkable similarities between amyloid β and an antimicrobial peptide (AMP) called LL37. I was browsing PubMed, just seeing where it would take me, when I found myself looking at LL37. In most ways, it is quite different from amyloid β, but in behavior the two are extremely similar – most notably, they both form amyloids. That made me dig deeper, and the closer I looked, the more it seemed like amyloid β’s activities mirrored those of AMPs, such as LL37. It essentially looked like a natural antibiotic.
How will your findings affect Alzheimer’s research?
I think it will have a major impact on therapeutic strategies. I’d suggest an analogy to cholesterol – high cholesterol can lead to heart disease, but you don’t want to remove it altogether or you’d run into all sorts of other problems. The aim should be to control amyloid β, not eliminate it. Our research also raises the possibility that infection is driving amyloidosis in Alzheimer’s disease. There are still quite a few questions to figure out with this theory but a large body of data has been gathering over the last few years to indicate that it may be true.
Do you think there’s more to discover about amyloid β?
Absolutely. I think this is the tip of the iceberg. AMPs are small and that’s often equated with simple, but that is as far from the truth as you can get. Among their many functions – and probably highly relevant for Alzheimer’s – is the ability to modulate the immune response. For example, amyloid β is known to be pro-inflammatory in Alzheimer’s but, a few years ago, a paper showed that it can actually be anti-inflammatory (2). I think this peptide is likely to play many other roles.
What’s next?
We’re pursuing several lines of enquiry. First, we’re investigating our suspicions that amyloid β is most active against viruses, versus bacteria or fungi. Secondly, we’re starting a venture called the Brain Microbiome Project, which will analyze the microbes contained in hundreds of brains, since we now know that the brain is not the sterile environment we once thought it was. Plus, we’re currently examining the development of antibiotics that can cross the blood–brain barrier. Finally, there are nearly 30 known amyloid-associated diseases, so we’re also looking to understand the underlying mechanisms of diseases like diabetes, to see if they share any similarities with Alzheimer’s.
- DK Kumar et al., “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease”, Sci Transl Med, 8, 340ra72 (2016). PMID: 27225182.
- JL Grant et al., “Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis”, Sci Transl Med, 4, 145ra105 (2012). PMID: 2855462.
My fascination with science, gaming, and writing led to my studying biology at university, while simultaneously working as an online games journalist. After university, I travelled across Europe, working on a novel and developing a game, before finding my way to Texere. As Associate Editor, I’m evolving my loves of science and writing, while continuing to pursue my passion for gaming and creative writing in a personal capacity.