{"id":304,"date":"2024-01-08T19:38:00","date_gmt":"2024-01-08T19:38:00","guid":{"rendered":"https:\/\/sebgc.es\/blog\/?p=304"},"modified":"2024-01-09T07:46:05","modified_gmt":"2024-01-09T07:46:05","slug":"this-one-microglia-mutation-could-triple-your-alzheimers-risk-heres-why","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2024\/01\/08\/this-one-microglia-mutation-could-triple-your-alzheimers-risk-heres-why\/","title":{"rendered":"This One Microglia Mutation Could Triple Your Alzheimer\u2019s Risk \u2013 Here\u2019s Why"},"content":{"rendered":"\n

A new study finds that microglia with mutant TREM2 protein reduce brain circuit connections, promote inflammation, and contribute to Alzheimer\u2019s pathology in other ways.<\/strong><\/p>\n\n\n\n

A rare but potent genetic mutation that alters a protein in the brain\u2019s immune cells, known as microglia, can give people as much as a threefold greater risk of developing Alzheimer\u2019s disease. A new study by researchers in The Picower Institute for Learning and Memory at MIT details how the mutation undermines microglia function, explaining how it seems to generate that higher risk.<\/p>\n\n\n\n

Study Insights on Microglia Dysfunction<\/h4>\n\n\n\n

\u201cThis TREM2 R47H\/+ mutation is a pretty important risk factor for Alzheimer\u2019s disease,\u201d says study lead author Jay Penney, a former postdoc in the MIT lab of Picower Professor Li-Huei Tsai. Penney is now an incoming assistant professor at the University of Prince Edward Island. \u201cThis study adds clear evidence that microglia dysfunction contributes to Alzheimer\u2019s disease risk.\u201d<\/p>\n\n\n\n

<\/a><\/p>\n\n\n\n

Bright green staining highlights implanted human microglia in mouse hippocampus tissue. Credit: Jay Penney\/Tsai Lab<\/p>\n\n\n\n

In the study in the journal GLIA<\/em>, Tsai and Penney\u2019s team shows that human microglia with the R47H\/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimer\u2019s pathology. Mutant microglia are prone to inflammation, yet are worse at responding to neuron injury and less able to clear harmful debris, including the Alzheimer\u2019s hallmark protein amyloid beta. And when the scientists transferred TREM2 mutant human microglia into the brains of mice, the mice suffered a significant decline in the number of synapses, or connections between their neurons, which can impair the circuits that enable brain functions such as memory.<\/p>\n\n\n\n

The study is not the first to ask how the TREM2 R47H\/+ mutation contributes to Alzheimer\u2019s, but it may advance scientists\u2019 emerging understanding, Penney says. Early studies suggested that the mutation simply robbed the protein of its function, but the new evidence paints a deeper and more nuanced picture. While the microglia do exhibit reduced debris clearance and injury response, they become overactive in other ways, such as their overzealous inflammation and synapse pruning.<\/p>\n\n\n\n

\u201cThere is a partial loss of function, but also a gain of function for certain things,\u201d Penney says.<\/p>\n\n\n\n

Misbehaving Microglia<\/h4>\n\n\n\n

Rather than rely on mouse models of TREM2 R47H\/+ mutation, Penney, Tsai, and their co-authors focused their work on human microglia cell cultures. To do this they used a stem cell line derived from skin cells donated by a healthy 75-year-old woman. In some of the stem cells they then used CRISPR gene editing to insert the R47H\/+ mutation and then cultured both edited and unedited stem cells to become microglia. This strategy gave them a supply of mutated microglia and healthy microglia, to act as experimental controls, that were otherwise genetically identical.<\/p>\n\n\n\n

The team then looked to see how harboring the mutation affected each cell line\u2019s expression of its genes. The scientists measured more than 1,000 differences, but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses. Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.<\/p>\n\n\n\n

<\/a><\/p>\n\n\n\n

Green staining in mouse hippocampus tissue indicates levels of a protein associated with synapses. The staining is noticeably brighter in a mouse that received healthy human microglia (control) than in a mouse that received mutant microglia. Credit: Jay Penney\/Tsai Lab<\/p>\n\n\n\n

In further experiments with the cells, the team exposed them to three kinds of the debris microglia typically clear away in the brain: myelin, synaptic proteins, and amyloid beta. The mutant microglia cleared less than the healthy ones.<\/p>\n\n\n\n

Another job of microglia is to respond when cells, such as neurons, are injured. Penney and Tsai\u2019s team co-cultured microglia and neurons and then zapped the neurons with a laser. For the next 90 minutes after the injury the team tracked the movement of surrounding microglia. Compared to normal microglia, those with the mutation proved less likely to head toward the injured cell.<\/p>\n\n\n\n

Finally, to test how the mutant microglia act in a living brain, the scientists transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. The scientists then stained that region to highlight various proteins of interest. Having mutant or normal human microglia didn\u2019t matter for some measures, but proteins associated with synapses were greatly reduced in mice where the mutated microglia were implanted.<\/p>\n\n\n\n

What Makes Microglia Tick?<\/h4>\n\n\n\n

By combining evidence from the gene expression measurements and the evidence from microglia function experiments, the researchers were able to formulate new ideas about what drives at least some of the microglial misbehavior. For instance, Penney and Tsai\u2019s team noticed a decline in the expression of a \u201cpurinergic\u201d receptor protein involving sensing neuronal injury, perhaps explaining why mutant microglia struggled with that task. They also noted that mice with the mutation overexpressed \u201ccomplement\u201d proteins used to tag synapses for removal. That might explain why mutant microglia were overzealous about clearing away synapses in the mice, Penney says, though increased inflammation might also cause that by harming neurons overall.<\/p>\n\n\n\n

As the molecular mechanisms underlying microglial dysfunction become clearer, Penney says, drug developers will gain critical insights into ways to target the higher disease risk associated with the TREM2 R47H\/+ mutation.<\/p>\n\n\n\n

\u201cOur findings highlight multiple effects of the TREM2 R47H\/+ mutation likely to underlie its association with Alzheimer\u2019s disease risk and suggest new nodes that could be exploited for therapeutic intervention,\u201d the authors conclude.<\/p>\n\n\n\n

Reference: \u201ciPSC-derived microglia carrying the TREM2 R47H\/+ mutation are proinflammatory and promote synapse loss\u201d by Jay Penney, William T. Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, Hannah Woolf and Li-Huei Tsai, 15 November 2023, Glia<\/em>.
DOI: 10.1002\/glia.24485<\/a><\/p>\n\n\n\n

In addition to Penney and Tsai, the paper\u2019s other authors are William Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, and Hannah Woolf.<\/p>\n\n\n\n

The Robert A. and Renee Belfer Family Foundation, The Cure Alzheimer\u2019s Fund, the\u00a0National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory, and the Human Frontier Science Program provided funding for the study.<\/p>\n\n\n\n

This One Microglia Mutation Could Triple Your Alzheimer\u2019s Risk \u2013 Here\u2019s Why (scitechdaily.com)<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

A new study finds that microglia with mutant TREM2 protein reduce brain circuit connections, promote inflammation, and contribute to Alzheimer\u2019s pathology in other ways. A rare but potent genetic mutation that alters a protein in the brain\u2019s immune cells, known as microglia, can give people as much as a threefold greater risk of developing Alzheimer\u2019s disease. A […]<\/p>\n","protected":false},"author":1,"featured_media":305,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1,5,19],"tags":[30],"class_list":["post-304","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-blog","category-noticias","category-sciencedaily","tag-alzheimer"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/304","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=304"}],"version-history":[{"count":1,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/304\/revisions"}],"predecessor-version":[{"id":306,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/304\/revisions\/306"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media\/305"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=304"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=304"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=304"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}