{"id":50788,"date":"2025-04-26T00:49:07","date_gmt":"2025-04-26T00:49:07","guid":{"rendered":"https:\/\/www.europesays.com\/uk\/50788\/"},"modified":"2025-04-26T00:49:07","modified_gmt":"2025-04-26T00:49:07","slug":"ai-uncovers-new-cause-of-alzheimers","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/uk\/50788\/","title":{"rendered":"AI Uncovers New Cause of Alzheimer\u2019s"},"content":{"rendered":"<p><strong>Summary: <\/strong>Researchers have discovered that a gene previously seen as a biomarker for Alzheimer\u2019s disease, PHGDH, actually plays a causal role by disrupting gene regulation in the brain. Using AI, the team revealed that PHGDH has a hidden DNA-binding function unrelated to its known enzymatic activity.<\/p>\n<p>This malfunction triggers early Alzheimer\u2019s development, offering a new target for prevention. They also identified a small molecule, NCT-503, that blocks this harmful activity without affecting normal brain chemistry.<\/p>\n<p><strong>Key Facts:<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li><strong>Hidden Role of PHGDH:<\/strong> AI revealed PHGDH acts as a DNA-binding disruptor, leading to Alzheimer\u2019s.<\/li>\n<li><strong>New Therapeutic Candidate:<\/strong> The small molecule NCT-503 blocks the harmful function without impairing normal activity.<\/li>\n<li><strong>Promising Results:<\/strong> Treated mice showed memory and anxiety improvements, suggesting clinical potential.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>UCSD<\/p>\n<p><strong>A new study found that a gene recently recognized as a biomarker for Alzheimer\u2019s disease is actually a cause of it, due to its previously unknown secondary function. <\/strong><\/p>\n<p>Researchers at the University of California San Diego used artificial intelligence to help both unravel this mystery of Alzheimer\u2019s disease and discover a potential treatment that obstructs the gene\u2019s moonlighting role.<\/p>\n<p>  <img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"801\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/04\/AI-Alzheimers-genetics-neuroscience.jpg\" alt=\"This shows a brain and DNA.\"  \/> When the researchers tested NCT-503 in two mouse models of Alzheimer\u2019s disease, they saw that it significantly alleviated Alzheimer\u2019s progression. Credit: Neuroscience News<\/p>\n<p>The research team published their results on April 23 in the journal\u00a0Cell.\u00a0<\/p>\n<p>About one in nine people aged 65 and older has Alzheimer\u2019s disease, the most common cause of dementia. While some particular genes, when mutated, can lead to Alzheimer\u2019s, that connection only accounts for a small percentage of all Alzheimer\u2019s patients.<\/p>\n<p>The vast majority of patients do not have a mutation in a known disease-causing gene; instead, they have \u201cspontaneous\u201d Alzheimer\u2019s, and the causes for that are unclear.<\/p>\n<p>Discovering those causes could ultimately improve medical care.<\/p>\n<p>\u201cUnfortunately, treatment options for Alzheimer\u2019s disease are very limited. And treatment responses are not outstanding at this moment,\u201d said study senior author Sheng Zhong, a professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.<\/p>\n<p>So Zhong and his team took a closer look at phosphoglycerate dehydrogenase (PHGDH), which they had previously\u00a0discovered as a potential blood biomarker\u00a0for early detection of Alzheimer\u2019s disease.<\/p>\n<p>In a follow-up study, they later found that\u00a0expression levels of the PHGDH gene directly correlated\u00a0with changes in the brain in Alzheimer\u2019s disease; in other words, the higher the levels of protein and RNA produced by the PHGDH gene, the more advanced the disease.<\/p>\n<p>That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong.<\/p>\n<p>Intrigued by this reproducible correlation, the research team decided to investigate in this latest study whether there was a causal effect.<\/p>\n<p>Using mice and human brain organoids, the researchers found that altering the amounts of PHGDH expression had consequential effects on Alzheimer\u2019s disease: lower levels corresponded to less disease progression, whereas increasing the levels led to more disease advancement.<\/p>\n<p>Thus, the researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer\u2019s disease.<\/p>\n<p>In further support of that finding, the researchers determined\u2014with the help of AI\u2014that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer\u2019s disease.<\/p>\n<p>Moonlighting role<\/p>\n<p>PHGDH creates an enzyme key for the production of serine, an essential amino acid and a neurotransmitter. Because PHGDH\u2019s enzymatic activity was its only known role, the researchers hypothesized that its metabolic function must be connected to an Alzheimer\u2019s outcome. However, all their experiments designed to prove so failed.\u00a0<\/p>\n<p>\u201cAt that time, our study hit a wall, and we didn\u2019t have a clue of what mechanism it is,\u201d said Zhong.<\/p>\n<p>But\u00a0another Alzheimer\u2019s project\u00a0in his lab, which did not focus on PHGDH, changed all this. A year ago, that project revealed a hallmark of Alzheimer\u2019s disease: a widespread imbalance in the brain in the process where cells control which genes are turned on and off to carry out their specific roles.\u00a0<\/p>\n<p>The researchers were curious if PHGDH had an unknown regulatory role in that process, and they turned to modern AI for help.<\/p>\n<p>With AI, they could visualize the three-dimensional structure of the PHGDH protein. Within that structure, they discovered that the protein has a substructure that is very similar to a known DNA-binding domain in a class of known transcription factors. The similarity is solely in the structure and not in the protein sequence.<\/p>\n<p>Zhong said, \u201cIt really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery.\u201d<\/p>\n<p>After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That throws off the delicate balance, leading to several problems and eventually the early stages of Alzheimer\u2019s disease.<\/p>\n<p>In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimer\u2019s disease.\u00a0<\/p>\n<p>That ties back to the team\u2019s earlier studies: the PHGDH gene produced more proteins in the brains of Alzheimer\u2019s patients compared to the control brains, and those increased amounts of the protein in the brain triggered the imbalance.<\/p>\n<p>While everyone has the PHGDH gene, the difference comes down to the expression level of the gene, or how many proteins are made by it.<\/p>\n<p>Treatment option<\/p>\n<p>Now that the researchers uncovered the mechanism, they wanted to figure out how to intervene and thus possibly identify a therapeutic candidate, which could help target the disease.\u00a0<\/p>\n<p>While many current treatments focus on treating the abnormal buildup of the sticky protein called beta-amyloid in the brain, some studies suggest that treating those plaques may be ineffective: essentially by that stage of accumulation, treatment is too late.<\/p>\n<p>But the critical pathway discovered in this study is upstream, so preventing this pathway can reduce amyloid plaque formation in the first place.<\/p>\n<p>Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH\u2019s enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic.<\/p>\n<p>They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH\u2019s regulatory role.<\/p>\n<p>When the researchers tested NCT-503 in two mouse models of Alzheimer\u2019s disease, they saw that it significantly alleviated Alzheimer\u2019s progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests.<\/p>\n<p>These tests were chosen because Alzheimer\u2019s patients suffer from cognitive decline and increased anxiety.<\/p>\n<p>The researchers do acknowledge limitations of their study. One being that there is no perfect animal model for spontaneous Alzheimer\u2019s disease. They could test NCT-503 only in the mouse models that are available, which are those with mutations in those known disease-causing genes.<\/p>\n<p>Still, the results are promising, according to Zhong.<\/p>\n<p>\u201cNow there is a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests,\u201d said Zhong. \u201cThere may be entirely new classes of small molecules that can potentially be leveraged for development into future therapeutics.\u201d<\/p>\n<p>An advantage of small molecules is that they could even be administered orally, he added, unlike the current treatments that require infusions.<\/p>\n<p>The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.<\/p>\n<p>About this AI and Alzheimer\u2019s disease research news<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#a2cecec3c0cbcdd1e2d7c1d1c68cc7c6d7\" target=\"_blank\" rel=\"noreferrer noopener\">Liezel Labios<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/ucsd.edu\" target=\"_blank\" rel=\"noopener\">UCSD<\/a><br \/><strong>Contact: <\/strong>Liezel Labios \u2013 UCSD<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/dx.doi.org\/10.1016\/j.cell.2025.03.045\" target=\"_blank\" rel=\"noreferrer noopener\">Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer\u2019s disease<\/a>\u201d by Sheng Zhong et al. Cell<\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer\u2019s disease<\/strong><\/p>\n<p>Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer\u2019s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele.<\/p>\n<p>This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients.<\/p>\n<p>We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity.<\/p>\n<p>PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology.<\/p>\n<p>A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH\u2019s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits.<\/p>\n<p>These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.<\/p>\n","protected":false},"excerpt":{"rendered":"Summary: Researchers have discovered that a gene previously seen as a biomarker for Alzheimer\u2019s disease, PHGDH, actually plays&hellip;\n","protected":false},"author":2,"featured_media":50789,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11],"tags":[323,231,1942,215,3725,267,105,3690,219,233,220,19405,16,15],"class_list":{"0":"post-50788","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-ai","9":"tag-alzheimers-disease","10":"tag-artificial-intelligence","11":"tag-brain-research","12":"tag-deep-learning","13":"tag-genetics","14":"tag-health","15":"tag-machine-learning","16":"tag-neurobiology","17":"tag-neurology","18":"tag-neuroscience","19":"tag-ucsd","20":"tag-uk","21":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/114401520164109353","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/50788","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=50788"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/50788\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/50789"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=50788"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=50788"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=50788"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}