{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:27:03Z","timestamp":1786724823598,"version":"build-2736575974"},"reference-count":75,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2025A1515011935"],"award-info":[{"award-number":["2025A1515011935"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["201704020222"],"award-info":[{"award-number":["201704020222"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["201807010094"],"award-info":[{"award-number":["201807010094"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010877","name":"Shenzhen Science and Technology Innovation Commission","doi-asserted-by":"crossref","award":["JCYJ20250604143459040"],"award-info":[{"award-number":["JCYJ20250604143459040"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China (NSFC)","doi-asserted-by":"crossref","award":["81671264"],"award-info":[{"award-number":["81671264"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) is the most common neurodegenerative disease with a rapid growth of patients worldwide in the aging era. Therefore, there is an urgent need to develop novel drugs for AD. Niacin and \u03b1-lipoic acid have been reported to exhibit therapeutic potential in AD through distinct biological activities, including GPR109A\/HCAR2 agonism and antioxidant effects, respectively. N2L, a hybrid molecule derived from \u03b1-lipoic acid and niacin and a known GPR109A\/HCAR2 agonist, has previously been reported to possess lipid-regulating, antiatherosclerotic, and ferroptosis-inhibitory properties. N2L is superior to niacin and\/or lipoic acid alone due to its longer half-life and the absence of flushing side effects. In this study, we evaluated the anti-AD efficacy of N2L in male mice, including both APP\/PS1 transgenic familial AD mice and acrolein-induced sporadic AD mice on the same C57BL\/6 background. N2L significantly attenuated amyloid-\u03b2 deposition, tau hyperphosphorylation, glial activation, synaptic degeneration, and ferroptosis in N2L-treated AD mice brains. Additionally, N2L increased the relative abundance of beneficial gut microbial taxa, including Lactobacillus, Bifidobacterium, and Faecalibaculum, suggesting a potential modulation of the microbiota\u2013gut\u2013brain axis. These findings demonstrate that N2L exerts multifaceted protective effects against AD-related pathological alterations and support its further development as a potential therapeutic candidate for AD.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00162","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:15:29Z","timestamp":1784524529000},"page":"2250-2265","source":"Crossref","is-referenced-by-count":0,"title":["A Niacin\u2212\u03b1-Lipoic\nAcid Hybrid Ameliorates\nAlzheimer\u2019s Disease Pathology in Mouse Models"],"prefix":"10.1021","volume":"9","author":[{"given":"Weijia","family":"Peng","sequence":"first","affiliation":[{"name":"Shenzhen Campus of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]},{"name":"International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong , ,","place":["Guangzhou, China, 510006"]},{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510060"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cailv","family":"Wei","sequence":"additional","affiliation":[{"name":"Shenzhen Campus of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiakai","family":"Pi","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenzhao","family":"Ding","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Guo","sequence":"additional","affiliation":[{"name":"The Seventh Affiliated Hospital of Sun Yat-sen University , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxu","family":"Chen","sequence":"additional","affiliation":[{"name":"Shenzhen Campus of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Shenzhen Campus of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]},{"name":"The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital , , ,","place":["Zhengzhou, China, 450008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8446-0404","authenticated-orcid":true,"given":"Runduo","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yin","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4808-1674","authenticated-orcid":true,"given":"Karl Wah-Keung","family":"Tsim","sequence":"additional","affiliation":[{"name":"The Hong Kong University of Science and Technology , , ,","place":["Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8150-9164","authenticated-orcid":true,"given":"Rongbiao","family":"Pi","sequence":"additional","affiliation":[{"name":"Shenzhen Campus of Sun Yat-sen University , , ,","place":["Shenzhen, China, 518107"]},{"name":"International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong , ,","place":["Guangzhou, China, 510006"]},{"name":"Guangdong Provincial Key Laboratory of Brain Function and Disease , ,","place":["Guangzhou, China, 510080"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"issue":"10","key":"2026081411080047100_cit1","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.4103\/1673-5374.308070","article-title":"Alzheimer\u2019s\ndisease: a tale of two diseases?","volume":"16","author":"Nardini","year":"2021","journal-title":"Neural Regener.\nRes."},{"issue":"2","key":"2026081411080047100_cit2","doi-asserted-by":"publisher","first-page":"135","DOI":"10.4103\/ijmr.IJMR_473_17","article-title":"New genetic players\nin late-onset\nAlzheimer\u2019s disease: Findings of genome-wide association studies","volume":"148","author":"Misra","year":"2018","journal-title":"Indian J. Med. Res."},{"issue":"1","key":"2026081411080047100_cit3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.4161\/pri.23061","article-title":"Prions, prionoids and\npathogenic proteins in Alzheimer\ndisease","volume":"7","author":"Ashe","year":"2013","journal-title":"Prion"},{"issue":"9516","key":"2026081411080047100_cit4","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/S0140-6736(06)68350-5","article-title":"Donepezil in patients\nwith severe Alzheimer\u2019s disease: double-blind, parallel-group,\nplacebo-controlled study","volume":"367","author":"Winblad","year":"2006","journal-title":"Lancet"},{"issue":"9","key":"2026081411080047100_cit5","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/s41582-025-01123-5","article-title":"Amyloid-lowering immunotherapies for Alzheimer disease:\ncurrent status and future directions","volume":"21","author":"Rafii","year":"2025","journal-title":"Nat. Rev.\nNeurol."},{"issue":"5","key":"2026081411080047100_cit6","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis:\nan iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"issue":"2","key":"2026081411080047100_cit7","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1002\/med.21712","article-title":"Mitochondria and\nlipid peroxidation\nin the mechanism of neurodegeneration: Finding ways for prevention","volume":"41","author":"Angelova","year":"2021","journal-title":"Med. Res. 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Brain Dis."},{"issue":"8","key":"2026081411080047100_cit19","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.18240\/ijo.2019.08.05","article-title":"Protective\neffects of lipoic acid-niacin dimers against\nblue light-induced oxidative damage to retinal pigment epithelium\ncells","volume":"12","author":"Zou","year":"2019","journal-title":"Int. J. Ophthalmol."},{"issue":"5","key":"2026081411080047100_cit20","doi-asserted-by":"publisher","first-page":"659","DOI":"10.13471\/j.cnki.j.sun.yat-sen.univ(med.sci).2021.0503","article-title":"Acrolein-induced Neuronal\nFerroptosis in Vitro and in Vivo: A Preliminary Study","volume":"42","author":"Peng","year":"2021","journal-title":"J. Sun Yat-sen Univ (Med. 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Res."},{"issue":"4","key":"2026081411080047100_cit24","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1007\/s13311-023-01376-2","article-title":"The Promise\nof Niacin in Neurology","volume":"20","author":"Wuerch","year":"2023","journal-title":"Neurotherapeutics"},{"issue":"637","key":"2026081411080047100_cit25","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl7634","article-title":"The niacin receptor HCAR2 modulates\nmicroglial response and limits disease progression in a mouse model\nof Alzheimer\u2019s disease","volume":"14","author":"Moutinho","year":"2022","journal-title":"Sci. Transl.\nMed."},{"issue":"2","key":"2026081411080047100_cit26","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/bmc.3006","article-title":"Determination of newly\nsynthesized lipoic acid-niacin\ndimer in rat plasma by UPLC\/electrospray ionization tandem mass spectrometry:\nassay development, validation and application to a pharmacokinetic\nstudy","volume":"28","author":"Chen","year":"2014","journal-title":"Biomed. Chromatogr."},{"issue":"4","key":"2026081411080047100_cit27","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13587","article-title":"Acrolein, an endogenous\naldehyde induces synaptic dysfunction in vitro and in vivo: Involvement\nof RhoA\/ROCK2 pathway","volume":"21","author":"Zhu","year":"2022","journal-title":"Aging Cell"},{"key":"2026081411080047100_cit28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.173361","article-title":"Discovery of a novel\nsmall molecule PT109 with multi-targeted effects against Alzheimer\u2019s\ndisease in vitro and in vivo","volume":"883","author":"Chen","year":"2020","journal-title":"Eur. J. Pharmacol."},{"issue":"5","key":"2026081411080047100_cit29","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1056\/NEJMc2215148","article-title":"Multiple Cerebral\nHemorrhages in a Patient Receiving Lecanemab and Treated with t-PA\nfor Stroke","volume":"388","author":"Reish","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"2026081411080047100_cit30","unstructured":"2025 Alzheimer\u2019s\ndisease facts and figures\n          Alzheimer\u2019s\nDementia\n          2025; Vol. 21e7023510.1002\/alz.70235."},{"issue":"10","key":"2026081411080047100_cit31","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15102382","article-title":"Conceptual\nFramework of the Design of Pleiotropic Drugs against Alzheimer\u2019s\nDisease","volume":"15","author":"Guiselin","year":"2023","journal-title":"Pharmaceutics"},{"issue":"2\u20133","key":"2026081411080047100_cit32","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1007\/s12035-010-8137-1","article-title":"Why pleiotropic\ninterventions are needed for Alzheimer\u2019s\ndisease","volume":"41","author":"Frautschy","year":"2010","journal-title":"Mol. Neurobiol."},{"issue":"12","key":"2026081411080047100_cit33","doi-asserted-by":"publisher","first-page":"3634","DOI":"10.1172\/JCI23626","article-title":"GPR109A (PUMA-G\/HM74A)\nmediates nicotinic acid-induced flushing","volume":"115","author":"Benyo\u0301","year":"2005","journal-title":"J.\nClin. Invest."},{"issue":"3","key":"2026081411080047100_cit34","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1056\/NEJMoa1300955","article-title":"Effects of\nextended-release niacin with laropiprant in high-risk patients","volume":"371","author":"Group","year":"2014","journal-title":"N Engl J. Med."},{"issue":"37","key":"2026081411080047100_cit35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2011226118","article-title":"NAD(+) supplementation\nreduces neuroinflammation and cell senescence in a transgenic mouse\nmodel of Alzheimer\u2019s disease via cGAS-STING","volume":"118","author":"Hou","year":"2021","journal-title":"Proc. Natl. Acad. 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Alzheimer\u2019s\nDis."},{"issue":"2","key":"2026081411080047100_cit41","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.neurobiolaging.2005.12.014","article-title":"Chronic dietary\nalpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576\nmice","volume":"28","author":"Quinn","year":"2007","journal-title":"Neurobiol. Aging"},{"issue":"16","key":"2026081411080047100_cit42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169186","article-title":"Redox Active\n\u03b1-Lipoic Acid\nDifferentially Improves Mitochondrial Dysfunction in a Cellular Model\nof Alzheimer and Its Control Cells","volume":"23","author":"Dieter","year":"2022","journal-title":"Int. J.\nMol. Sci."},{"key":"2026081411080047100_cit43","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.00262","article-title":"\u03b1-Lipoic Acid Maintains Brain Glucose Metabolism\nvia BDNF\/TrkB\/HIF-1\u03b1 Signaling Pathway in P301S Mice","volume":"12","author":"Zhang","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"2026081411080047100_cit44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2025.108241","article-title":"Lipoic acid scaffold\napplications in the design of multitarget-directed ligands against\nAlzheimer\u2019s disease","volume":"157","author":"Manavi","year":"2025","journal-title":"Bioorg. Chem."},{"issue":"1","key":"2026081411080047100_cit45","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-022-00292-3","article-title":"Immunotherapy for Alzheimer\u2019s\ndisease: targeting \u03b2-amyloid and beyond","volume":"11","author":"Song","year":"2022","journal-title":"Transl. Neurodegener."},{"issue":"3","key":"2026081411080047100_cit46","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28031168","article-title":"Neuroprotective\nEffect of \u03b1-Lipoic Acid against\nA\u03b2(25\u201335)-Induced Damage in BV2 Cells","volume":"28","author":"Pei","year":"2023","journal-title":"Molecules"},{"key":"2026081411080047100_cit47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2023.114790","article-title":"Alpha-lipoic acid reduces nociception\nby reducing oxidative\nstress and neuroinflammation in a model of complex regional pain syndrome\ntype I in mice","volume":"459","author":"Rodrigues","year":"2024","journal-title":"Behav. Brain Res."},{"issue":"6","key":"2026081411080047100_cit48","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1002\/acn3.414","article-title":"Effects\nof fumarates on inflammatory\nhuman astrocyte responses and oligodendrocyte differentiation","volume":"4","author":"Galloway","year":"2017","journal-title":"Ann. Clin. 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