Role of Garlic Usage in Cardiovascular Disease Prevention: An Evidence‐Based Approach
Breakthroughs In Alzheimer's Research May Be Game-changers
Research on Alzheimer's disease is approaching a much-needed tipping point. The media spotlight has been on newly available drugs like lecanemab and donanemab that target the protein plaques associated with the disease's progression. But a burgeoning consensus is emerging around a longstanding hypothesis that was once considered unorthodox and quixotic: Infections may trigger or exacerbate Alzheimer's disease and other neurological conditions.
It's a straightforward hypothesis with profound implications for how we diagnose and treat a debilitating disease that impacts nearly 7 million Americans (and about 55 million people worldwide). Health-care and caregiving costs associated with Alzheimer's disease are believed to exceed $600 billion annually.
A hallmark of Alzheimer's disease, the most common form of dementia globally, is chronic brain inflammation. For decades, Alzheimer's disease researchers have searched for a missing puzzle piece: What drives this inflammation?
Now, spurred by the prolonged neurological symptoms that many people experienced after COVID-19 infections, such as brain fog and loss of their sense of smell, scientists are more focused on infection as an underlying driver of inflammation across the human body.
Numerous bacteria, viruses, fungi, and parasites are capable of entering the brain. One example is the bacterium that causes Lyme disease. Another is an airborne bacterium, Chlamydia pneumoniae, that was first found in Alzheimer's-diseased brains by Dr. Balin and colleagues as far back as 1998. Other microbes, such as those residing in the gut or the mouth, may impact and inflame the brain by triggering body-wide inflammatory responses.
The fact that some bacteria appear to protect some people against this inflammation only reinforces the complex and important relationship between humans and our many invisible passengers.
This extends beyond dementia and Alzheimer's disease. Several neurological conditions, including multiple sclerosis, have been linked with infections or changes in the collection of microbes inside all of us, but establishing a causal relationship has remained elusive.
Even so, there are case reports in medical journals of "reversible dementias" caused by infections. In these reports, doctors identified underlying infections, and patients improved drastically once they received targeted treatments.
Knowing all this, why aren't we more focused on testing and treatments for potential infectious drivers of inflammatory diseases? There are three key reasons.
- Medical paradigm shifts are notoriously slow. Rather than targeting potential root causes of Alzheimer's disease, drug developers have largely worked to reduce the disease's progression, such as by targeting the plaques of the protein amyloid that can show up in the brain. Another example of this phenomenon was the rise of profitable drugs for stomach ulcers that didn't treat the root cause. (It was later discovered that a bacterium, Helicobacter pylori, was causing the ulcers.)
- Drugs that fight infection are among the least profitable for the drug industry. This reduces investors' appetite for funding preventive approaches to treating (or potentially curing) diseases associated with chronic infection, despite the growing need for such options.
- The science is complicated. It's hard to demonstrate that a microbe or infection causes a disease. Microbes can be stealthy, testing tools are imperfect, and responses to a single infection can vary greatly from person to person — as we know well from collective experience with COVID-19. Also, chronic diseases unfold over many years and involve multiple variables, making them difficult to study.
Still, there is cause for hope.
Earlier this year, before the Alzheimer's Association International Conference in Philadelphia, a group of scientists gathered a few miles away at Philadelphia College of Osteopathic Medicine (PCOM) as part of the Alzheimer's Pathobiome Initiative. Joining scientists at PCOM were colleagues from Baylor, Columbia, Drexel, Harvard and Massachusetts General Hospital, The Hebrew University in Jerusalem, Oxford, Pittsburgh, and Tulane, among others — all sharing findings that point to the significance of the so-called "infection hypothesis" in Alzheimer's disease and other neurological diseases.
Recently, our research group highlighted how infection can interfere with senses such as vision, hearing, and smell, causing them to malfunction in a possible early warning sign of Alzheimer's disease.
The growth of this scientific community, and its collaborative spirit, reflect the level of compelling evidence already accumulated, as well as the urgency of the cause. Global cases of dementia are expected to nearly double every 20 years, each case taking a profound toll on the patient and their loved ones.
We're at the edge of a breakthrough in understanding conditions ranging from Parkinson's disease to mental illness. After decades without effective treatments, people are listening, and scientists are taking action.
Nikki Schultek is executive director of the Alzheimer Pathobiome Initiative (AlzPI) and founder of Intracell Research Group. In remission from chronic infection, she worked in the pharmaceutical industry before focusing on interdisciplinary research and advocacy.
Brian J. Balin, PhD, is professor of neuroscience and neuropathology and director of the center for chronic disorders of aging at Philadelphia College of Osteopathic Medicine (PCOM). He is internationally recognized in the field of Alzheimer's disease research and is a founding member of the Alzheimer's Pathobiome Initiative (AlzPI).
Uncovering The Unexpected: Developing A Novel Anti-Tau Therapy
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and researchers now attribute its symptoms to the deposition of tau amyloid fibrils. Although scientists developed many therapeutics that are effective in vitro, most of these drugs have shown limited success in clinical trials, with some of these failures due to inefficient delivery to the brain.
Ke Hou, a postdoctoral fellow in David Eisenberg's laboratory at the University of California, Los Angeles, is devising innovative approaches to improve the transportation of AD treatments across the blood-brain barrier (BBB). In a recently published Science Advances paper, Hou and her team modified their existing therapeutic peptide, which binds to tau fibrils and inhibits their growth in vitro, to conjugate it to magnetic nanoparticles (MNPs).1 Unexpectedly, these changes also allowed the complex to act as a disaggregator of tau fibrils.
Ke Hou and her colleagues developed a seven-residue peptide conjugated to magnetic nanoparticles, where this complex both inhibits tau aggregation and fragments existing tau fibrils in the brain.
Ke Hou
Why have the previous anti-tau therapies shown limited efficacy in vivo?
For decades, researchers have produced numerous AD drugs targeting amyloid beta only for them to fail in clinical trials. Scientists have only shifted focus more recently to developing anti-tau therapies. Of the tau aggregation inhibitors and antibodies that they have generated so far, many of them do not efficiently cross the BBB, which limits their bioavailability. Additionally, some of the therapeutic antibodies can cause serious side effects.
Before I joined the group, the Eisenberg team used tau's structure to design a six-residue, D-enantiomeric peptide (6-DP). However, the group hypothesized that this tau aggregation inhibitor would not be able to penetrate the BBB. Because my background is in material science, I could conjugate the peptide to nanomaterials, such as MNPs, and test the efficiency of the complex to prevent tau aggregation in mouse brains.
Why did you choose to use MNPs as a drug carrier?
MNPs can efficiently cross the BBB, which could help improve the peptide's delivery to the brain. Additionally, the US Food and Drug Administration had already approved an MNP-based therapy for the treatment of chronic kidney disease, suggesting that the carriers are well tolerated. This nanomaterial also has superparamagnetic properties, which means that the peptide-MNP complex could serve as a diagnostic AD probe for magnetic resonance imaging.
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Cell & Molecular Biology
Modeling the Blood-Brain Barrier in a Dish
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What happened when you conjugated the peptide to the MNPs?
To easily attach the peptide to the nanoparticles, I needed to add one extra cysteine to the end of the 6-DP, forming a seven-residue peptide (7-DP). When I tested the properties of the peptide-MNP complex in vitro, it not only could prevent tau aggregation but could also disassemble existing tau fibrils. To determine which component was responsible for this surprising function, we examined the abilities of the nanoparticle and peptides alone and found that the 7-DP but not the MNPs or 6-DP could disaggregate heparin-induced tau fibrils and pathological tau fibrils that we extracted from human brain tissue. We also assessed the effects of the peptide-MNPs on an AD mouse model and observed that the complex transversed the BBB and led to reduced tau pathology in their brains and improved memory function. This suggests that the peptide-MNPs could reverse AD's progression.
We wanted to figure out why the one cysteine difference between the 6-DP and the 7-DP enabled the peptide to have this disaggregation property, so we started evaluating its potential mechanism and have summarized our results in a pre-print posted on bioRxiv.2 We determined that the 7-DP can self-aggregate forming a right-handed fibril. When the peptide binds to and aggregates onto the left-handed tau fibrils, the 7-DP initially conforms to its left-handed twist. However, the peptide must reverse its twist to relieve the torsional strain and by doing so disrupts the tau fibril, enabling its fragmentation.
What are your next steps?
We are currently characterizing the fragments produced after the 7-DP disassembles tau fibrils using mass spectrometry and electron microscopy. We know that these fragments cannot seed the growth of new tau fibrils, so we would like to learn more about their structure. We also are using the information we learned from this study to design disaggregators against other amyloid fibrils, such as alpha-synuclein, and hopefully develop drugs for other neuronal diseases.
This interview has been condensed and edited for clarity.
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Microbiology
Gut Microbe Metabolites Lower Levels of Toxic Tau
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The Pathophysiology Of Chronic Graft-Vs -Host Disease (cGVHD) And The Role Of CSF1R
Opinion
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December 23, 2024Sergio A. Giralt, MD, discusses how the pathophysiology of chronic graft-vs-host disease involves complex immune dysregulation, with CSF1R playing a crucial role in driving the differentiation of monocytes into macrophages, contributing to inflammation and fibrosis in the disease.
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Describe the pathophysiology of chronic graft-vs-host disease and the role of CSF1R in disease pathogenesis.
December 21st 2024 ICYMI: Highlights From ASCO 2024
Top coverage from the 2024 American Society of Clinical Oncology (ASCO) annual meeting included research topics in non-small cell lung cancer (NSCLC), multiple myeloma, metastatic colorectal cancer (mCRC), and more.
December 12th 2024 ICYMI: Highlights From ACTRIMS 2024
Read about the diverse array of research presented at this year's meeting, including novel technological advancements and insights into disease progression in multiple sclerosis (MS).
December 21st 2024 ICYMI: Highlights From ASCO 2024
Top coverage from the 2024 American Society of Clinical Oncology (ASCO) annual meeting included research topics in non-small cell lung cancer (NSCLC), multiple myeloma, metastatic colorectal cancer (mCRC), and more.
December 12th 2024 ICYMI: Highlights From ACTRIMS 2024
Read about the diverse array of research presented at this year's meeting, including novel technological advancements and insights into disease progression in multiple sclerosis (MS).
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