{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:39:02Z","timestamp":1785411542109,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,23]]},"group-title":"Pharmacology and Toxicology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["MLP-6002 (WP-4)"],"award-info":[{"award-number":["MLP-6002 (WP-4)"]}],"id":[{"id":"https:\/\/ror.org\/01zw2nq07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in\n                  <jats:italic>Curcuma longa<\/jats:italic>\n                  , stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of\n                  <jats:italic>AMPK<\/jats:italic>\n                  . Additionally, BDMC-induced autophagy aided in the removal of amyloid beta that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC can significantly penetrate the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg\/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. Additionally, we discovered that the treated mice\u2019s hippocampus had a significantly lower amyloid beta load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                      <jats:caption>\n                        <jats:p>This illustration was created by using biorender.com<\/jats:p>\n                      <\/jats:caption>\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"654834v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                    <\/jats:fig>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.19.654834","type":"posted-content","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T01:30:21Z","timestamp":1748050221000},"source":"Crossref","is-referenced-by-count":2,"title":["Bisdemethoxycurcumin mitigates Alzheimer disease pathology through autophagy-mediated reduction of senescence and amyloid beta"],"prefix":"10.64898","author":[{"given":"Parul","family":"Khajuria","sequence":"first","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilpreet","family":"Kour","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuhu","family":"Sharma","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakhvinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razia","family":"Banoo","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"},{"name":"Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu-180016, India"},{"name":"Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad-500007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diksha","family":"Manhas","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Ramajayan","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utpal","family":"Nandi","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"},{"name":"Chemical Sciences, Unified Academic Campus, Bose Institute, EN-80, Sector V, Bidhan Nagar, Kolkata - 700 091, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandip","family":"Bharate","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"},{"name":"Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu-180016, India"},{"name":"Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad-500007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zabeer","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Kumar","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu- 180016, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041123074314000_2025.05.19.654834v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"2026041123074314000_2025.05.19.654834v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1044-y"},{"key":"2026041123074314000_2025.05.19.654834v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt155"},{"key":"2026041123074314000_2025.05.19.654834v1.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6412-10.2011"},{"key":"2026041123074314000_2025.05.19.654834v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3232"},{"key":"2026041123074314000_2025.05.19.654834v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0244-7"},{"key":"2026041123074314000_2025.05.19.654834v1.7","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.7567"},{"key":"2026041123074314000_2025.05.19.654834v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature16187"},{"key":"2026041123074314000_2025.05.19.654834v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature13619"},{"key":"2026041123074314000_2025.05.19.654834v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.07.030"},{"key":"2026041123074314000_2025.05.19.654834v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12122"},{"key":"2026041123074314000_2025.05.19.654834v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1182228"},{"key":"2026041123074314000_2025.05.19.654834v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nature08221"},{"key":"2026041123074314000_2025.05.19.654834v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/nature13013"},{"key":"2026041123074314000_2025.05.19.654834v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.34"},{"key":"2026041123074314000_2025.05.19.654834v1.16","doi-asserted-by":"crossref","unstructured":"D\u2019adda Di Fagagna , F. Living on a break: cellular senescence as a DNA-damage response. Nature Reviews Cancer 2008, 8 (7), 512\u2013522.","DOI":"10.1038\/nrc2440"},{"key":"2026041123074314000_2025.05.19.654834v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.09.015"},{"key":"2026041123074314000_2025.05.19.654834v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.11.010"},{"key":"2026041123074314000_2025.05.19.654834v1.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi3450"},{"key":"2026041123074314000_2025.05.19.654834v1.20","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2021.1909260"},{"key":"2026041123074314000_2025.05.19.654834v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0372-9"},{"key":"2026041123074314000_2025.05.19.654834v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.04.029"},{"key":"2026041123074314000_2025.05.19.654834v1.23","doi-asserted-by":"publisher","DOI":"10.7150\/thno.79535"},{"key":"2026041123074314000_2025.05.19.654834v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.0c02607"},{"key":"2026041123074314000_2025.05.19.654834v1.25","doi-asserted-by":"crossref","unstructured":"Sikora, E. ; Bielak-Zmijewska, A. ; Dudkowska, M. ; Krzystyniak, A. ; Mosieniak, G. ; Wesierska, M. ; Wlodarczyk, J . Cellular senescence in brain aging. Frontiers in aging neuroscience 2021, 13, 646924.","DOI":"10.3389\/fnagi.2021.646924"},{"key":"2026041123074314000_2025.05.19.654834v1.26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64098"},{"key":"2026041123074314000_2025.05.19.654834v1.27","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1247143"},{"key":"2026041123074314000_2025.05.19.654834v1.28","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4521-10.2010"},{"issue":"5","key":"2026041123074314000_2025.05.19.654834v1.29","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/aps.2012.194","article-title":"Coordination of autophagy with other cellular activities","volume":"34","year":"2013","journal-title":"Acta Pharmacologica Sinica"},{"key":"2026041123074314000_2025.05.19.654834v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00579-5"},{"key":"2026041123074314000_2025.05.19.654834v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0101-y"},{"key":"2026041123074314000_2025.05.19.654834v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6659"},{"key":"2026041123074314000_2025.05.19.654834v1.33","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14593"},{"key":"2026041123074314000_2025.05.19.654834v1.34","doi-asserted-by":"publisher","DOI":"10.5607\/en.2019.28.6.643"},{"key":"2026041123074314000_2025.05.19.654834v1.35","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Cu\u00e9, C. ; Rueda, N. Cellular senescence in neurodegenerative diseases. Frontiers in cellular neuroscience 2020, 14, 16.","DOI":"10.3389\/fncel.2020.00016"},{"key":"2026041123074314000_2025.05.19.654834v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2024.149202"},{"key":"2026041123074314000_2025.05.19.654834v1.37","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201810248"},{"key":"2026041123074314000_2025.05.19.654834v1.38","unstructured":"Kempuraj, D. ; Thangavel, R. ; Natteru, P. ; Selvakumar, G. ; Saeed, D. ; Zahoor, H. ; Zaheer, S. ; Iyer, S. ; Zaheer, A. Neuroinflammation induces neurodegeneration. Journal of neurology, neurosurgery and spine 2016, 1 (1)"},{"key":"2026041123074314000_2025.05.19.654834v1.39","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01008"},{"key":"2026041123074314000_2025.05.19.654834v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature09932"},{"key":"2026041123074314000_2025.05.19.654834v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.032"},{"key":"2026041123074314000_2025.05.19.654834v1.42","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1872187"},{"key":"2026041123074314000_2025.05.19.654834v1.43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1418422"},{"key":"2026041123074314000_2025.05.19.654834v1.44","doi-asserted-by":"crossref","unstructured":"Kour, D. ; Khajuria, P. ; Sharma, K. ; Sharma, A. ; Sharma, A. ; Ali, S. M. ; Wazir, P. ; Ramajayan, P. ; Sawant, S. D. ; Nandi, U. Isobavachalcone ameliorates Alzheimer disease pathology by autophagy-mediated clearance of amyloid beta and inhibition of NLRP3 inflammasome in 5XFAD mice. 2023.","DOI":"10.21203\/rs.3.rs-3762830\/v1"},{"key":"2026041123074314000_2025.05.19.654834v1.45","doi-asserted-by":"publisher","DOI":"10.38212\/2224-6614.3454"},{"key":"2026041123074314000_2025.05.19.654834v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2891-13-11"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.19.654834","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T06:07:48Z","timestamp":1775974068000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.19.654834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":46,"URL":"https:\/\/doi.org\/10.1101\/2025.05.19.654834","relation":{},"subject":[],"published":{"date-parts":[[2025,5,23]]},"subtype":"preprint"}}