LongeCityNews Last Updated: 26 December 2025 - 02:23 AM

As researchers note in today's materials, there is clear an association between periodontal disease and the progression of atherosclerosis. Atherosclerosis is universal in older humans, the growth of fatty lesions in blood vessel walls that ultimately impede circulating blood flow to a fatal degree or rupture to cause stroke and heart attack. The degree of atherosclerosis at a given age is highly variable across the human population, however. The degree to which atherogenic processes in any two individuals are driven by the same stimulus, such as increased LDL cholesterol levels or increased lipoprotein A levels or increased inflammation, can be very different. This makes it somewhat challenging to talk about how much of a problem any given atherogenic issue actually poses.

This is much the case for periodontitis and its contribution to atherosclerosis. One can demonstrate mechanisms that in principle allow periodontitis to make inflammatory diseases worse elsewhere in the body, primarily that bacteria and their inflammatory metabolites can leak into circulation via the injured gums. But it is a step from there to find good correlational data in human studies, let alone data that convincingly puts a number to the degree of risk produced by periodontitis. Still, avoiding chronic inflammation in later life is well established to be a beneficial goal for a wide range of reasons. Chronic inflammation is disruptive to tissue structure and function in many contexts, and wherever reasonable efforts can be taken to reduce sources of inflammation, the results should be worth it.

Gum disease may be linked to plaque buildup in arteries, higher risk of major CVD events

Although periodontal disease and atherosclerotic cardiovascular disease (ASCVD) share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.

Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease, and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed. There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD.

Periodontal Disease and Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association

Direct mechanisms of the association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) are thought to be through bacteremia and vascular infection. Dental plaque in periodontal disease contains multiple bacterial strains. Periodontal pockets, with manipulation of the tissue, can result in bleeding, which allows periodontal bacteria to enter systemic circulation. Once in the bloodstream, pathogens can trigger a systemic inflammatory response. This, along with increased vascular permeability, could lead to endothelial dysfunction. Endothelial dysfunction can be a sign of early subclinical atherosclerosis.

Bacteremia from chronic periodontal infections may increase the inflammatory burden that accelerates atherogenesis. Inflammation due to direct oral microbiome actions may affect systemic inflammation of blood vessel walls through two modes: direct invasion of bacteria through the diseased and inflamed periodontal tissues into the general circulation and phagocyte-mediated bacterial translocation. The oral microbiome thereby invades vascular tissues, which may experience acute inflammation, which, in the absence of complete resolution, could lead to chronic inflammation and ASCVD.

Researchers here identify FOXF2 as necessary to maintain function of the vascular endothelium that lines blood vessels and the blood-brain barrier that wraps blood vessels passing through the brain to protect the distinct environment of the brain from cells and molecules that would disrupt it. They hypothesize that reduced levels of FOXF2 or related dysfunction in the expression and activity of genes it influences, such as TIE2, are an important contribution to the vascular dysfunctions that make up cerebral small vessel disease.

Researchers have genetically modified mice so that only their endothelial cells lack the ability to produce certain proteins. Endothelial cells form the innermost lining of blood vessels and they are the site where small vessel disease often begins. By selectively switching off the Foxf2 gene - previously identified by the researchers as a stroke risk gene - these cells lack the corresponding protein, leading to impaired function of small cerebral vessels, especially disruption of the blood-brain barrier, which protects the brain from harmful influences.

Foxf2 is a transcription factor that activates many other genes - including, as researchers discovered, the gene Tie2 and its downstream components in the so-called Tie signaling pathway. In endothelial cells, activation of the Tie2 gene and proper functioning of the Tie2 pathway are crucial for maintaining vascular health. Without Tie2, for example, the risk of inflammatory reactions in the endothelial cells of larger vessels increases, which in turn promotes atherosclerosis and raises the risk of stroke and dementia.

The researchers tested a therapy targeting the impaired function of small cerebral vessels based on their new insights. The drug candidate AKB-9778 specifically activates Tie2. "I would love to announce that we are already preparing a clinical study to test this compound in patients. However, at the moment it is not easy to access the substance, as it is currently being evaluated in clinical trials for use in other conditions." The team is now searching for related compounds that could be developed for clinical testing in small vessel disease.

Link: https://www.lmu.de/en/newsroom/news-overview/news/stroke-and-dementia-combating-loss-of-function-in-small-vessels-of-the-brain-1313fe47.html

Research into the role of amyloid-β in Alzheimer's disease has shifted somewhat to focus on the surrounding biochemistry rather than the aggregates, now that clearing the aggregates via immunotherapies is an ongoing concern, and has shown less of a benefit to patients than hoped. As researchers note here, there is evidence for specific amyloid-β oligomers to be the most toxic consequence of having too much amyloid-β in general. Researchers have developed a drug that reduces levels of one of the problem oligomers, and this study is one of the early tests of its ability to help in an animal model of Alzheimer's disease.

One possible reason for the failure of early Alzheimer's disease (AD) clinical trials is that treatments were initiated after symptom onset, when pathology is already widespread. Another contributing factor, especially for amyloid-β (Aβ) targeting therapies, is that most treatments have selectively targeted monomeric or fibrillar forms of Aβ, which are not the most toxic species. Soluble amyloid-β oligomers (AβOs), which form prior to plaques, are widely regarded as the most toxic Aβ species.

One proposed mechanism by which early AβOs contribute to AD is by activation of immune cells. AβOs can activate glia in culture and in wild type rodent or primate brain following injection, but their role in initiating gliosis early in AD remains unclear. Since glial activation is among the primary events in AD, identifying molecules that trigger gliosis is critical for diagnostics and therapeutics.

In this study, we investigated early pathology in 5xFAD mice. Results showed distinct AβO subtypes differing in localization, morphology, and association with key AD hallmarks such as degenerating neurons, plaques, phosphorylated TDP-43 (pTDP-43), and activated immune cells. We report an AβO subtype that associates with the earliest degenerating neurons and activated immune cells and provide support for its role in early neuronal degeneration and astrogliosis. Furthermore, we validate the in vivo efficacy of NU-9, a drug-like compound recently shown to inhibit AβO accumulation in cultured hippocampal neurons. Oral NU-9 treatment significantly reduced ACU193+ AβOs on reactive astrocytes and rescued astrocyte glial fibrillary acidic protein (GFAP) levels, suggesting astrocyte-associated AβOs may induce reactive astrogliosis. We predict that neutralization of ACU193+ AβOs early in AD could slow or prevent disease progression.

Link: https://doi.org/10.1002/alz.70968

The innate immune system becomes increasingly inflammatory with age, in part due to damage and dysfunction in immune cells, in part a maladaptive reaction to a damaged environment. Chronic inflammation is disruptive to tissue structure and function. Macrophages make up a sizable fraction of the innate immune system, resident in tissues and involved in both tissue maintenance and defense against pathogens. A broad range of research is focused on better understanding and potentially manipulating macrophage behavior to obtain desired outcomes, such as a lower level of chronic inflammation in later life.

In today's open access paper, researchers focus on the macrophages resident in fat tissue. Visceral fat is a source of inflammation, and this is one of the reasons why being overweight is increasingly bad for health as life progresses into older age. This research illuminates one of the regulatory elements involved in increasing inflammatory behavior in macrophages in fat tissue, raising its profile as a potential target for anti-inflammatory therapies, and contributing to the bigger picture of inflammatory mechanisms in visceral fat tissue.

GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging

Older individuals have increased risk for infections and subsequent sepsis, in part owing to accumulating adiposity and a dysfunctional immune system. Gerotherapeutics that successfully improve the aged immune response are largely understudied. Our study reveals that the GDF3-SMAD2/3 axis may be a relevant pharmacologic target. GDF3 promotes the inflammatory phenotype of adipose tissue macrophages, contributing to the exacerbation of endotoxemia-induced inflammation in older, but not younger, organisms. GDF3 signals through SMAD2/3 and elicits proinflammatory responses in adipose tissue macrophages, diverging from their canonical immunoregulatory function.

Specifically, the chromatin landscape of adipose tissue macrophages shifts toward inflammation with age, increasing the accessibility of inflammation-associated genes. Our study demonstrates that Gdf3 deficiency can reverse the age-dependent changes in chromatin accessibility and transcription by restoring H3K27me3 levels in adipose tissue macrophages. Furthermore, genetic and pharmacological inhibition targeting the GDF3-SMAD2/3 axis protects against endotoxemia-induced inflammation and lethality in old mice.

The importance of visceral adipose tissue (VAT) in aging and inflammation is corroborated by studies that highlight the immunological role of VAT during metabolic challenge or infection in older organisms. Recent work indicates that B cells-derived IgG elevates macrophage expression of Tgfb, which promotes fibrosis and metabolic decline via SMAD2/3 in aged VAT. Our work builds on this model, providing additional evidence for the importance of B cell-macrophage crosstalk in VAT. We also provide evidence for the GDF3-SMAD2/3 axis regulating the phenotype of B cells. Although it remains unclear whether GDF3 acts synergistically with TGFβ-superfamily cytokines, our findings indicate that the mechanism governing inflammatory VAT microenvironment, driven by adipose tissue macrophages and B cells, may converge on SMAD2/3 signaling.