{"id":30417,"date":"2021-04-15T00:00:17","date_gmt":"2021-04-15T07:00:17","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=30417"},"modified":"2024-01-30T14:35:47","modified_gmt":"2024-01-30T22:35:47","slug":"in-surprising-twist-some-alzheimers-plaques-may-be-protective-not-destructive","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/in-surprising-twist-some-alzheimers-plaques-may-be-protective-not-destructive\/","title":{"rendered":"In surprising twist, some Alzheimer\u2019s plaques may be protective, not destructive"},"content":{"rendered":"

LA JOLLA\u2014One of the characteristic hallmarks of Alzheimer\u2019s disease (AD) is the buildup of amyloid-beta plaques in the brain. Most therapies designed to treat AD target these plaques, but they\u2019ve largely failed in clinical trials. New research by Salk scientists upends conventional views of the origin of one prevalent type of plaque, indicating a reason why treatments have been unsuccessful.<\/p>\n

The traditional view holds that the brain\u2019s trash-clearing immune cells, called microglia, inhibit the growth of plaques by \u201ceating\u201d them. The Salk scientists show instead that microglia promote the formation of dense-core plaques, and that this action sweeps wispy plaque material away from neurons, where it causes cell death. The research, which was published in Nature Immunology<\/em><\/a> on April 15, 2021, suggests that dense-core plaques play a protective role, so treatments to destroy them may do more harm than good.<\/p>\n

\"A
A dense-core amyloid-beta plaque (red) surrounded by microglia that lack TAM receptors (white) in the brain of a mouse with Alzheimer\u2019s disease.
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cWe show that dense-core plaques don’t form spontaneously. We believe they’re built by microglia as a defense mechanism, so they may be best left alone,\u201d says Greg Lemke<\/a>, a professor in Salk\u2019s Molecular Neurobiology Laboratory. \u201cThere are various efforts to get the FDA to approve antibodies whose main clinical effect is reducing dense-core plaque formation, but we make the argument that breaking up the plaque may be doing more damage.\u201d<\/p>\n

Alzheimer\u2019s disease is a neurological condition that results in memory loss, impairment of thinking, and behavioral changes, which worsen as we age. The disease seems to be caused by abnormal proteins aggregating between brain cells to form the hallmark plaques, which interrupt activity that keeps the cells alive.<\/p>\n

There are numerous forms of plaque, but the two most prevalent are characterized as \u201cdiffuse\u201d and \u201cdense-core.\u201d Diffuse plaques are loosely organized, amorphous clouds. Dense-core plaques have a compact center surrounded by a halo. Scientists have generally believed that both types of plaque form spontaneously from excess production of a precursor molecule called amyloid precursor protein (APP).<\/p>\n

But, according to the new study, it is actually microglia that form dense-core plaques from diffuse amyloid-beta fibrils, as part of their cellular cleanup.<\/p>\n

This builds on a 2016 discovery<\/a> by the Lemke lab, which determined that when a brain cell dies, a fatty molecule flips from the inside to the outside of the cell, signaling, \u201cI\u2019m dead, eat me.\u201d Microglia, via surface proteins called TAM receptors, then engulf, or \u201ceat\u201d the dead cell, with the help of an intermediary molecule called Gas6. Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.<\/p>\n

The team\u2019s current work shows that it\u2019s not only dead cells that exhibit the eat-me signal and Gas6: So do the amyloid plaques prevalent in Alzheimer\u2019s disease. Using animal models, the researchers were able to demonstrate experimentally for the first time that microglia with TAM receptors eat amyloid plaques via the eat-me signal and Gas6. In mice engineered to lack TAM receptors, the microglia were unable to perform this function.<\/p>\n

Digging deeper, they traced the dense-core plaques using live imaging. Much to their surprise, the team discovered that after a microglial cell eats a diffuse plaque, it transfers the engulfed amyloid-beta to a highly acidic compartment and converts it into a highly compacted aggregate that is then transferred to a dense-core plaque. The researchers propose that this is a beneficial mechanism, organizing diffuse into dense-core plaque and clearing the intercellular environment of debris.<\/p>\n

\"From
From left: Greg Lemke and Youtong Huang
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cOur research seems to show that when there are fewer dense-core plaques, there seem to be more detrimental effects,\u201d says Youtong Huang, first author on the paper. \u201cWith more-diffuse plaques, there’s an abundance of dystrophic neurites, a proxy for neuronal damage. I don’t think there\u2019s a distinct clinical decision on which form of plaque is more or less detrimental, but through our research, we seem to find that dense-core plaques are a bit more benign.\u201d<\/p>\n

Their findings suggest new ways of developing a treatment for Alzheimer\u2019s disease, such as boosting expression of TAM receptors on microglia to accelerate dense-core plaque formation. The team would like to conduct cognitive studies to see if increasing the activity of microglial TAM receptors would alleviate the effects of AD.<\/p>\n

Lemke, who holds the Fran\u00e7oise Gilot-Salk Chair, believes that the current failure rate of most Alzheimer\u2019s drug trials is about to end. \u201cSome people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain,\u201d says Lemke.\u00a0 \u201cBut we argue that amyloid-beta is still clearly a bad thing; it’s just that you\u2019ve got to ask whether dense-core plaques are a bad thing.\u201d<\/p>\n

Lemke suggests that scientists looking for a cure for Alzheimer\u2019s should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.<\/p>\n

Other authors on the study are Kaisa E. Happonen, Patrick G. Burrola, Carolyn O\u2019Connor, Nasun Hah, Ling Huang, and Axel Nimmerjahn of Salk.<\/p>\n

The work was supported by grants from the US National Institutes of Health; the Cure Alzheimer\u2019s Fund; the Coins for Alzheimer\u2019s Research Trust; the Leona M. and Harry B. Helmsley Charitable Trust; UC San Diego Goeddel\u2019s Chancellor\u2019s, Marguerite Vogt, and the H.A. and Mary K. Chapman Charitable Trust graduate fellowships; and Anderson, NOMIS Foundation and Sweden-America Foundation postdoctoral fellowships.<\/p>","protected":false},"featured_media":30461,"template":"","faculty":[96],"disease-research":[459,146],"class_list":["post-30417","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-greg-lemke","disease-research-glial-biology","disease-research-aging-and-regenerative-medicine"],"acf":[],"yoast_head":"\nIn surprising twist, some Alzheimer\u2019s plaques may be protective, not destructive - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/in-surprising-twist-some-alzheimers-plaques-may-be-protective-not-destructive\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"In surprising twist, some Alzheimer\u2019s plaques may be protective, not destructive - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014One of the characteristic hallmarks of Alzheimer\u2019s disease (AD) is the buildup of amyloid-beta plaques in the brain. 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