Your Brain is What Makes You – You (presented by Dr. Donald Weaver)
By Sophia Linton, PhD Candidate and TMED 801 Course TA
Dr. Donald Weaver, MD, PhD, FRCPC, was Neurology's guest Medical Grand Round (MGR) speaker this week. He spoke about reconceptualizing Alzheimer's Disease (AD) as an innate autoimmune disease. He also met with members of the TMED graduate program for a round table discussion about his research, career, and much more.
Dr. Weaver began by communicating that AD is a disease that comes with major societal problems because it affects an estimated 50 million individuals worldwide. Its prevalence is expected to triple by 2050. He added that AD also comes with a neuropharmacological problem: the current lack of disease-modifying drugs on the market because AD is a neurodegenerative disorder whose etiology has not been fully defined and for which there is no cure. However, the neuropathological hallmarks of AD brains are well known, including the accumulation of amyloid-β (Aβ) protein in neuritic plaques and neurofibrillary tangles consisting of hyper-phosphorylated tau proteins, all in the milieu of chronic inflammation(1).
Traditional mechanistic proposals for the etiology of AD have primarily focused on proteopathy, specifically the amyloid protein misfolding hypothesis, and have been tested in trials of anti-amyloid antibodies, none of which have been successful(2). In his talk, Dr. Weaver presented compelling evidence from his laboratory that Aβ is an immunopeptide that can be incorporated with proteopathy into a broader-based immunopathic model of AD. He described in silico and in vitro studies of Aβ membrane interactions that suggest Aβ behaves like an antimicrobial peptide and is a molecular trigger of innate immunity. He also showed that adding copper (Cu2+), zinc (Zn2+) ions, and cholesterol further enhanced Aβ's ability to penetrate and destroy cell membranes; these are well-known characteristics of immunopeptides. He explained that his next step was to elucidate a mechanism for the disease chronicity seen in AD within innate immunity and, to this end, discovered that Aβ-killed necrotic neurons release molecules that propagate necrosis in other neurons, ultimately creating a self-perpetuating cycle of inflammation or autoimmunity.
Considering AD as an auto-autoimmune disorder allowed Dr. Weaver to search for endogenous factors in the brain with anti-Aβ activity. He screened 1137 molecules, conducted many follow-up experiments to evaluate potential anti-immunopathic effects, and found that tryptophan metabolite analogues were promising candidates for novel anti-AD therapeutic designs. He also searched for an alternative platform to synthetic tryptophan metabolites by screening natural and pre-existing drug products that exhibit Aβ anti-aggregate activities and contain tryptophan-like moieties. This search showed that a drug called furosemide, a common and cheap diuretic, appeared to have promising anti-proteopathic and anti-immunopathic bioactivities(3). Without giving away any spoilers, Dr. Weaver explained that he is exploring the possibility of bringing a furosemide analogue to future clinical trials. This formidable research by Dr. Weaver is published here: https://doi.org/10.1002/trc2.12283. It's also worth mentioning that Dr. Weaver is collaborating with KGH Research Institute's own Dr. John Muscedere to trial furosemide for treating COVID-19 in a study funded by LifeArc Charities (click here to read more: https://kingstonhsc.ca/research/news/teaching-old-drug-new-tricks-commonly-used-medication-repurposed-treat-covid-19).
After the MGR, Dr. Weaver graciously sat down for a round table discussion with TMED students. Here, students were able to ask questions about how his research directly benefited patients, how it was represented in the lay-press and/or Equity, Diversity, Inclusivity, and Indigeneity initiatives, and finally his career path. Dr. Weaver emphasized that his background in Theoretical Chemistry made him and his laboratory uniquely qualified to study endogenous analogues as a therapeutic strategy for AD, a direction that has not been previously evaluated to date. He also held a great appreciation for his training and perspective as a Neurologist. He said that it allowed him to work and perform research using many disciplines, resources, and techniques at the intersection of bench side, bedside, and community which truly the embodiment of translational medicine. Dr. Weaver’s involvement in the foundations of six biotech start-up companies is an example of his strengths in translating research from the laboratory to the market.
On behalf of the students in TMED, I would like to extend a warm thank you to Dr. Weaver for taking the time to speak with us. Thank you for reminding us that we must never forget that the brain is what makes you – you.
1. Wu J, Li L. Autoantibodies in Alzheimer’s disease: Potential biomarkers, pathogenic roles, and therapeutic implications. Vol. 30, Journal of Biomedical Research. 2016.
2. Knopman DS. Lowering of Amyloid-Beta by β-Secretase Inhibitors — Some Informative Failures. New England Journal of Medicine [Internet]. 2019;380(15):1476–8. Available from: https://doi.org/10.1056/NEJMe1903193
3. Meier-Stephenson FS, Meier-Stephenson VC, Carter MD, Meek AR, Wang Y, Pan L, et al. Alzheimer’s disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites. Translational Research and Clinical Interventions. 2022 Apr;8(1).