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Dr. Don Weaver

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. 
 

References:

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).

Comments

Name
Sophia Linton

Tue, 09/20/2022 - 10:59

Thanks everyone for reading my blog post. I hope you enjoyed it. I welcome students from the TMED class (or any reader who comes across the posting), to leave comments or questions.

Name
Sophia Linton

Name
Abhishek Shastry

Tue, 09/20/2022 - 12:18

Hi Sophia,
I appreciate your summary of Dr. Weaver's lecture and roundtable discussion with us during last week's class. As you mentioned, Dr. Weaver outlined a multi-step strategy to investigate amyloid-β's (Aβ) antimicrobial properties, including in silico, in vitro, and in vivo arms. The in silico arm included a visualization and characterization of Aβ's electrostatic interactions to neural membranes and outlined the structural basis for its immunopathology. I was wondering if you could comment on the effectiveness of preliminary in silico studies in characterizing unknown pathologies based on known protein structural properties, based such factors such as cost? How well do in silico studies translate to in vitro findings?

Thank you!

-Abhishek

Name
Abhishek Shastry

Hi Abhishek,

Thanks for your question.

I am no expert when it comes to in silico studies, and so I'll defer my answer to this quotation from the journal, Frontiers: "Computer-aided drug design (CADD) methodologies are playing an ever-increasing role in drug discovery that are critical in the cost-effective identification of promising drug candidates. These computational methods are relevant in limiting the use of animal models in pharmacological research, for aiding the rational design of novel and safe drug candidates, and for repositioning marketed drugs, supporting medicinal chemists and pharmacologists during the drug discovery trajectory."

In terms of translating research findings from in silico studies to in vitro, there are a relevant number of papers in the literature which are focused on different ligand- and structure-based approaches or on a combination thereof to identify promising molecules for a given target. This approach is seen in Dr. Weaver's research.

https://www.frontiersin.org/articles/10.3389/fchem.2020.00612/full

Name
Sophia Linton

Name
Sam Delios

Tue, 09/20/2022 - 15:39

Hi Sophia,

Thank you for your summary and post! During this MGR, it was great to hear from Dr. Weaver about his expertise in Alzheimer's disease (AD). He discussed AD as an innate autoimmune disease and looked into 4 anti-AD therapeutic design approaches (tryptophan metabolite analogues) to help target this disease. I wondered out of all 4 approaches if you could comment on which you believe would be the most promising application for the AD model. I also wondered if you could comment on why you believe furosemide was considered for use in one approach rather than any other anti-inflammatory drugs, anti-Immunopathic drugs, or drugs with similar properties for drug repurposing. Overall, this was an amazing presentation and I really appreciate Dr. Weaver taking the time to come and speak with our class.

Thank you for your post!

Name
Sam Delios

Hi Sam,

Thanks for your comment and question.

In my opinion, a potential furosemide analogue would be a strong candidate to advance to clinical trials. I am basing this decision on the cost (furosemide is cheap and commonly used) and that the timeline is potentially shorter than that of a de novo designed compound.

According to Dr. Weaver's article, referenced in my post, they performed a screen of anti-inflammatory compounds that have tryptophan moieties. Furosemide must tick each of these boxes as well as other the requirements in their screen.

Sophia

Name
Sophia Linton

Name
Jill Greenlaw

Tue, 09/20/2022 - 16:59

Hi Sophia,

Thanks for your excellent summary of Dr. Weaver’s talk! I really liked how you highlighted that while the societal effects of AD are widespread and its prevalence is increasing, there remains a lack of successful treatment options for AD. As indicated by the title of your blog post, the brain defines who you are, rendering the effects of AD absolutely devastating for patients and their families. In your opinion, what (scientific or societal) barriers do you think have impeded further advancement of AD treatment & the development of therapeutics?

Looking forward to hearing your thoughts!

Jill

Name
Jill Greenlaw

Hi Jill,

I am very glad you brought up this excellent point.

Something that was mentioned in the lecture and our rounds discussion was the widespread lack of success in amyloid reducing therapeutics, for example β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE-1) inhibitors.

I wonder if these failures in amyloid-based targets (which has really dominated AD research over the past few decades) has negatively impacted new research coming up.

What do you think?

Sophia

Name
Sophia Linton

Name
Matti McFarlane

Tue, 09/20/2022 - 17:47

Hi Sophia!

Thank you for your insightful summary of the first MGR of this school year. I found that Dr. Weaver was an excellent lecturer and clearly provided an overview of the Alzheimer’s Disease (AD) research landscape. A point of interest from the lecture was the broad theoretical approaches to the underlying etiology of AD. Certain pathological hallmarks have been identified and agreed upon by leading scientists such as: 1) Presence of amyloid-β aggregates in the formation of dense plaques; 2) aggregation of tau protein into neurofibrillary tangles (NFTs); 3) chronic brain inflammation (1). However, as highlighted in our discussions, the current pharmaceutical options for AD are unfavourable for chronic use, primarily targeting symptomatic improvement rather than disease modification (2). Particularly, the drug aducanumab (the first new treatment for AD in two decades), is a controversial development in the treatment of AD. Despite inconclusive clinical trial evidence for the drug’s clinical benefits, it gained accelerated FDA approval for use in AD patients (2). I found this especially of interest, as Dr. Weaver had discussed the current difficulty in ascertaining funding and approval for AD pharmaceuticals. Aducanumab is an excellent case study of the ethical dilemmas scientists face, when they must weigh the risks and benefits of new treatments. Certainly, with a disease that effects what makes you who you are, the promise of a disease modifying agent could warrant accelerated approval. Currently, aducanumab requires intravenous infusion approximately every 4 weeks, a somewhat arduous treatment for patients (2). In your opinion, do you feel that the FDA approval of aducanumab was warranted? Or should more rigorous testing confirming certain clinical benefit (especially with chronic use) be ensured?

Thank you again for your thoughts. The efforts of clinician-scientists such as Dr. Weaver certainly provide a hopeful future for the treatment of AD!

Best,

Matti

References

1. Autoantibodies in Alzheimer’s disease: potential biomarkers, pathogenic roles, and therapeutic implications. J Biomed Res [Internet]. 2016 Sep 30 [cited 2022 Sep 20]; Available from: http://www.jbr-pub.org.cn/en/article/doi/10.7555/JBR.30.20150131

2. Dunn B, Stein P, Cavazzoni P. Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective. JAMA Internal Medicine. 2021 Oct 1;181(10):1276–8.

Name
Matti McFarlane

Thanks Matti,

All great points were mention in your comment. Well done.

Wow, a quick google search of aducanumab comes up with so much controversy. Obviously, I am no expert in this field, but look at this article titled "Why Physicians Should Not Prescribe Aducanumab for Alzheimer Disease" - that is a bold statement (link here: https://www.aafp.org/pubs/afp/issues/2022/0400/p353.html).

I would absolutely agree that clinically meaningful benefits to patients and that data regarding benefits need to be seen before approval...

I look forward to seeing more news about this drug in the future.

Sophia

Name
Sophia Linton

Name
Abby Mocherniak

Wed, 09/21/2022 - 21:02

Hi Sophia,
This was a great read, and fantastic summary of last week's MGR! Your blog post highlighted the growing need for therapeutic interventions to treat, diagnose, and improve the quality of life for individuals with Alzheimer's disease (AD). This is especially critical considering our globally aging population. The presentation given in MGR hit very close to home for me, as I have watched family members suffer the effects of Alzheimer's disease progression. This allowed me to understand the notion of your brain making you who you are, to a greater degree.

Given that lifestyle factors have been noted to contribute to the development of AD (approximately 33% of AD cases), I am curious how you think socioeconomic status may also play a role in the development of AD (1)? Recent publications indicate that dementia tends to be more prevalent in low-income countries, accompanied by earlier age of disease onset (2). This indicates that a potential link may exist between socioeconomic status and brain health, posing the question of whether the same may be observed for AD.

Best,
Abby

1. Mayeda, E. R., Glymour, M. M., Quesenberry, C. P., & Whitmer, R. A. (2016). Inequalities in dementia incidence between six racial and ethnic groups over 14 years. Alzheimer’s and Dementia, 12(3), 216–224. https://doi.org/10.1016/J.JALZ.2015.12.007
2. Resende, E. D. P. F., Llibre Guerra, J. J., & Miller, B. L. (2019). Health and Socioeconomic Inequities as Contributors to Brain Health. JAMA Neurology, 76(6), 633–634. https://doi.org/10.1001/JAMANEUROL.2019.0362

Name
Abby Mocherniak

Name
Sophia Linton

Thu, 09/22/2022 - 15:19

In reply to by Abby M. (not verified)

Hi Abby,

Thank you very much for bringing up these points. I am sorry you have had to experience the effects AD in your family.

I found this very interesting paper published in the British Journal of Psychiatry. They sought to to examine the association between socioeconomic status in early life and adulthood with later dementia death. So, they performed an individual participant meta-analysis of 11 prospective cohort studies (1994-2004, n = 86 508) and saw that Leaving full-time education at an earlier age was associated with an increased risk of dementia death in women (fully adjusted hazard ratio (HR) for age ⩽14 v. age ⩾16: HR = 1.76, 95% CI 1.23-2.53) but not men. Occupational social class was not statistically significantly associated with dementia death in men or women.

More studies are needed to look into this very important topic.

Sophia

Name
Sophia Linton

Name
Future directions for testing novel therapeutics

Thu, 09/22/2022 - 13:07

Hi Sophia,
Thank you for your thoughtful and insightful post on Dr. Weaver's amazing lecture. As a student that is interested in studying the pharmacology of novel therapies (specifically for treating pain in the GI tract, in my case), I found Dr. Weaver's presentation quite eye opening. It is still awe-inspiring to see the amount of time and effort it may take to bring a new drug just to Phase I clinical trials and hearing the experiences of Dr. Weaver has given me a newfound perspective and appreciation for the long path I have ahead of me with the novel drug we are studying at GIDRU, NFEPP.

When hearing about Dr. Weaver's in vitro and in silico studies, it sparked some connections with the work I do in the lab. In fact, NFEPP, the drug I am studying, was also first developed in an in silico model of the acidified microenvironment that exists in inflammation of tissues! I'm wondering what his next steps would be for his work using the Aß peptide, specifically in an in vivo model. Considering that our program thrives on translational research, I am always thinking about ways to bring bench work (in vitro, in silico, etc.) into more translational models, whether that be humans or animals. The most prominent in vivo model of AD, from my literature search, uses Rhesus macaques (Stonebarger et al., 2021). Do you think moving into an animal model using non-human primates is the appropriate next-step for Dr. Weaver's research? Or, considering animal welfare and the Three R's, should we stick to cell work and computer modelling until we are certain of our findings?

Name
Future directions for testing novel therapeutics

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