Friday, September 29, 2023

New perspectives on understanding, preventing and treating vascular dementia

CCR5 expression in response to oxidative stress is mediated by NF-κB. (A) Upper: Schematic overview of the murine Ccr5 gene. Blue boxes represent introns, pink boxes exons, and yellow boxes (A and B) putative NF-κB/p65 binding elements. Lower: Chromatin immunoprecipitation using an NF-κB/p65 antibody of wild-type neurons after H2O2 (30μM) or vehicle (Ct) treatment. The input samples represent equal fractions of DNA extract collected prior to immunoprecipitation. (B) Ccr5 mRNA levels measured by real-time PCR in wild-type neurons pretreated with the NF-κB inhibitor BAY 11-7082 and treated with H2O2 (30μM). #p<0.05 using two-way ANOVA followed by Tukey post-hoc test (n=4). (C) Nuclear localization of NF-κB/p65 staining in control (Ct) and H2O2-treated Ccr5+/+ and Ccr5-/- primary neurons analyzed by an automated image program. §§p<0.01 as compared to the respective control, using one-way ANOVA followed by Tukey post-hoc test. (D) Confocal fluorescence microscopy showing cell morphology (phase contrast), nuclear counterstaining with DAPI (orange) and NF-κB/p65 staining (green). In the merged images, the nuclear localization of NF-κB is indicated in yellow (Scale bar=10μm). Credit: Alzheimer’s & Dementia (2023). DOI: 10.1002/alz.13392

Dementia is a group of brain diseases that share similar symptoms, such as memory, language, orientation, and behavioral issues. Vascular dementia generally develops in the elderly, affecting between 1% and 4% of people over the age of 65, according to Alzheimer’s Switzerland. It is caused by vascular lesions that disrupt the blood supply to the brain, leading to the death of neurons.

There is currently no cure for vascular , and the only way to combat it is prevention by controlling such as , high cholesterol, diabetes and smoking. Preventive measures would become more effective with the discovery of new disease biomarkers that would enable a better identification of people at risk. And this is what the HUG and UNIGE team succeeded in by discovering the role of the CCR5 receptor in the development of vascular dementia.

A new biomarker for dementia

Now published in Alzheimer’s & Dementia, the study focused on CCR5, a receptor protein linked to chemokines, chemical messengers of the immune system. The team led by Dina Zekry, Head of the division of Internal Medicine for the Aged at the HUG and Associate Professor in the Department of Rehabilitation and Geriatrics at the UNIGE Faculty of Medicine, in collaboration with the team led by Karl-Heinz Krause, a senior physician in the Department of Diagnostics and Medicine at the HUG and Full Professor in the Department of Pathology and Immunology at the UNIGE Faculty of Medicine, who were both responsible for the study.

They discovered that CCR5 plays a crucial role in brain cells response to oxidative stress, a mechanism involved in the death of neurons. They also found a link between a specific genetic variant of CCR5 and that of another protein, apolipoprotein E (ApoE), known for its role in age-related dementia.

This complex genetic association considerably increases the risk of vascular dementia. “People over the age of 80 who carry this specific genotype are eleven times more likely to develop ,” explains Benjamin Tournier, Ph.D., a biologist in the Department of Psychiatry at the HUG, and a researcher in the Department of Psychiatry at the UNIGE Faculty of Medicine and first author of the study.

This research of translational nature, a concept that aims to translate fundamental discoveries into concrete clinical applications, has made it possible to clarify the probable mechanisms of dementia through a series of experiments. The research team first highlighted the potential role of CCR5 in ischemic mechanisms by examining mouse neurons “in vitro.”

They then studied variations in the CCR5 and ApoE genes in a group of 362 people (205 without dementia and 189 with dementia) who agreed to give blood samples annually for a duration of five years. These findings were then verified on another cohort in Italy (157 individuals without dementia and 620 individuals with dementia), consolidating the robustness of the discovery.

Prof Zekry emphasizes the importance of this discovery as a new target for understanding and treating age-related dementia. “This is a major advance that opens doors for the early identification of individuals at risk and for the development of targeted therapies. It offers considerable hope for our society with regard to neurocognitive diseases as a whole.” New treatment strategies could also emerge from these results aiming at improving the quality of life and functionality of those affected.

More information:
Benjamin B. Tournier et al, CCR5 deficiency: Decreased neuronal resilience to oxidative stress and increased risk of vascular dementia, Alzheimer’s & Dementia (2023). DOI: 10.1002/alz.13392

Provided by
Hôpitaux Universitaires de Genève

New perspectives on understanding, preventing and treating vascular dementia (2023, September 4)
retrieved 4 September 2023

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