{"id":24107,"date":"2024-09-02T11:53:00","date_gmt":"2024-09-02T17:53:00","guid":{"rendered":"https:\/\/canadianglycomics.ca\/?p=24107"},"modified":"2024-09-14T10:33:01","modified_gmt":"2024-09-14T16:33:01","slug":"new-study-yields-significant-insight-into-a-major-driver-of-alzheimers-disease","status":"publish","type":"post","link":"https:\/\/canadianglycomics.ca\/fr\/new-study-yields-significant-insight-into-a-major-driver-of-alzheimers-disease\/","title":{"rendered":"New study yields significant insight into a major driver of Alzheimer\u2019s Disease"},"content":{"rendered":"\t\t
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New study yields significant insight into a major driver of Alzheimer\u2019s Disease<\/h1>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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GlycoNet researchers find that CD33 isoforms on the surface of the brain’s microglia can have opposing effects, providing protection or increased susceptibility to Alzheimer’s Disease.\u00a0 \u00a0\u00a0<\/span><\/em><\/p>

By Donna McKinnon\u00a0 \u2022\u00a0 Posted: September 2, 2024<\/span><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t

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Photo of microglia in red surrounding an amyloid plaque in blue from \"CD33 isoforms in microglia and Alzheimer's disease: Friend and fow\" by Ghazaleh Eskandari-Sedighi, Jaesoo Jung and Matthew S. Macauley.<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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In the Dementia Canada: Economic Burden<\/a>\u00a0report, issued in 2022 by the Canadian Centre for Economic Analysis, the total annual economic burden of dementia in Canada is estimated to be $40 billion. If the current trend holds, this burden could grow by 275 per cent over the next 30 years. Delaying the onset of dementia by one, five, or 10 years would reduce the annual burden in 2050 by 10, 42, and 70 per cent, respectively.<\/p>

Under the umbrella of dementia, Alzheimer’s Disease (AD) is the most common form of neurodegenerative disease. While environmental factors play a role, approximately 70 per cent of AD risk is attributable to genetics.<\/p>

A\u00a0new study<\/a>\u00a0led by\u00a0Ghazaleh Eskandari-Sedighi<\/a>, a postdoctoral researcher, and GlycoNet investigator Matthew Macauley<\/a> in the Department of Chemistry at University of Alberta, has shown that CD33, a carbohydrate-binding protein receptor on the surface of microglia (the brain\u2019s immune cells) does not just skew susceptibility to the development of AD in mice, but in its shorter isoform, may also serve as protection against the disease.<\/p>

Understanding these opposing susceptibility factors is a step toward the development of therapeutic interventions.\u00a0<\/p>

The paradox of human CD33<\/strong><\/p>

One of the most significant revolutions in the study of complex diseases like Parkinson\u2019s and Alzheimer’s, explains Eskandari-Sedighi, is the development of genome-wide association studies (GWAS), which collect and compare millions of complete sets of DNA to find genetic variations and trends associated with particular diseases.<\/p>

\u201cGWAS hits are like diamonds,\u201d she says. \u201cYou dig deep, and when you find something meaningful, you focus on it. CD33 was one of those hits.\u201d<\/p>

Microglia are crucial for modulating cognition, memory, behaviour, gene expression, and other neurological functions. CD33, an immunomodulatory receptor on the surface of microglia, helps immune cells interact with disease pathogens. Along with APOE e4, it is considered a top-ranked driver in the development of AD, but as their study shows, CD33 in its long isoform (CD33M) and short isoform (CD33m) have dramatic and opposing effects on the development of AD.\u00a0<\/p>

The research was, by necessity, cross-disciplinary \u2014 spanning the faculties of\u00a0Science<\/a>\u00a0and\u00a0Medicine & Dentistry<\/a>\u00a0with experts in single cell transcriptomics (Jason Plemel<\/a>),\u00a0proteomics<\/a>\u00a0(Oliver Julien<\/a>), neurology and behaviour (Qiumin Tan<\/a>), and biochemistry (Valerie Sim<\/a>).\u00a0<\/p>

\u201cAlzheimer\u2019s is a very complex disease, with many cell types involved,\u201d says Macauley. \u201cIt\u2019s impossible to model in a petri dish \u2014 and you need to be able to monitor it longitudinally, because realistically, the important part of the development of AD in humans happens 30 years prior to the onset of symptoms. The solution was creating transgenic mice that express either version of CD33 to understand what the microglia are doing in AD pathology, which is when plaques [abnormal clusters of protein fragments] develop and how the microglia is responding.\u201d<\/p>

As Eskandari-Sedighi notes, in humans both forms of the CD33 protein isoform are present but the ratios differ. When the short isoform dominates, it overrules the negative effect of the long isoform.<\/p>

A plaque is not just a plaque\u00a0<\/strong><\/p>

\u201cWhen we started working in this area, we thought of plaques as being bad, but it\u2019s more complicated than that because a lot of people develop plaques who don\u2019t go on to develop AD,\u201d says Macauley. \u201cIt\u2019s about how the microglia immune cells respond to those plaques, and how the immune cells then shape the plaques. One of Ghazaleh\u2019s major contributions is that a plaque is not just a plaque \u2014 its density is a very important factor. I like to use the garbage analogy \u2014 if you let your garbage spread out, you’d be living in garbage. So, we put it in the trash and landfills to keep it contained. That\u2019s what people in the neuroimmunology field postulate the microglia are doing \u2014 they are helping to compact the plaques. As Ghazaleh noted, the protective\u00a0short<\/em>\u00a0form of CD33 endowed the microglia with the ability to compact. The converse is also true; the\u00a0long<\/em>\u00a0version of CD33 that makes you more susceptible did the opposite. It made them less compact, and more diffuse.\u201d<\/p>

Eskandari-Sedighi says Macauley\u2019s novel model of separating the isoforms and studying their impact on microglial cells independent of each other was critical to understanding the mechanism behind one of the most significant drivers of AD.<\/p>

\u201cEverybody considered CD33 a risk, but our study showed it\u2019s not just risk and absence of risk, it\u2019s actually risk and protection,\u201d she says. \u201cIt brings in benefits through the mechanisms that Matt mentioned \u2014 making plaques more dense. And that was being missed.\u201d<\/p>

\u201cA huge percentage of AD risk goes back to immune response and microglia, and that\u2019s why this work, on top of all other research that is currently underway in this field, is important; so that we can understand the mechanisms that lead to disease pathogenesis \u2014 basically, whether someone gets the disease or not,\u201d says Eskandari-Sedighi. \u201cIf we can understand that, then hopefully we can design therapeutics.\u201d<\/p>

This study was funded by the\u00a0<\/em>Alzheimer Society of Canada<\/em><\/a>\u00a0and the\u00a0<\/em>Alzheimer Society of Alberta and Northwest Territories,<\/em><\/a>\u00a0in collaboration with\u00a0<\/em>Campus Alberta<\/em><\/a>, the\u00a0<\/em>Canadian Institutes of Health Research<\/em><\/a>\u00a0(CIHR) and the<\/em> Canadian Glycomics Network (GlycoNet)<\/em><\/a>.\u00a0<\/em>Matthew Macauley is a member of the\u00a0<\/em>Neuroscience and Mental Health Institute<\/em><\/a>.<\/em><\/p><\/div>

Reposted from the University of Alberta’s Faculty of Science News<\/a>.<\/em><\/p><\/div>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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Discover more from GlycoNet News.<\/a><\/h6>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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GlycoNet researchers find that CD33 isoforms on the surface of the brain’s microglia can have opposing effects, providing protection or increased susceptibility to Alzheimer’s Disease. <\/p>","protected":false},"author":8,"featured_media":24108,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"elementor_header_footer","format":"standard","meta":{"om_disable_all_campaigns":false,"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[203],"tags":[208,280,7,272,281,209],"class_list":["post-24107","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-research-highlight","tag-alzheimer","tag-alzheimers-disease","tag-glyconet","tag-matthew-macauley","tag-microglia","tag-neurodegenerative-disease","wpbf-post"],"aioseo_notices":[],"aioseo_head":"\n\t\t\n\t\n\t\n\t\n\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t\n\t\t