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This study focused on repurposing the FDA-approved drug, Voglibose to target the DKK1-LRP6 site with the goal of upregulating WSP in in vitro as well as rodent model of AD. Based on our previous computational approach, Voglibose was evaluated for the DKK1 binding, neuroprotective effects were examined using SHSY5Y cells, while WSP activation was analyzed through RTPCR in the HEK293\/LRP6 cell line. Rodent model of AD was developed using intracerebroventricular administration of A\u03b2<jats:sub>25-35<\/jats:sub>. Male Wistar rats were randomly assigned to receive oral doses of Voglibose (1 and 10\u00a0mg\/kg) for 28\u00a0days, after which behavioral assessments, biochemical analyses, RT-PCR, and histopathological evaluations were conducted. Voglibose showed significant reduction in the DKK1 binding, neuroprotective property in SHSY5Y as well as activation of WSP in LRP6 overexpressed HEK293 cells. There was a significant decrease in the island latency in rats treated with lower dose (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and higher dose (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) of Voglibose when compared to the disease control rats. Similarly, in the behavioral tests, Voglibose significantly improved cognition. The deposition of amyloid plaques was found to be considerably more in the disease control rats which got reduced in the treatment groups as observed in the histopathological slides stained with Congo red. Significant alterations in mRNA levels and protein expression of glycogen synthase kinase-\u03b2 (GSK-3\u03b2), \u03b2-catenin (\u03b2-cat) was observed in rat brain homogenates indicating upregulation of WSP. In conclusion, Voglibose demonstrated significant neuroprotective potential in a cell line study and showed potential cognitive benefits in a rat model of AD. Furthermore, its ability to activate WSP highlights its immense potential as AD therapeutic to enhance memory and modulate key neuroprotective mechanisms.<\/jats:p>","DOI":"10.1007\/s12035-025-05047-5","type":"journal-article","created":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T09:34:54Z","timestamp":1747474494000},"page":"12184-12204","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Voglibose Attenuates Amyloid Beta\u2013Induced Memory Deficits in a Rodent Model: A Potential Alzheimer\u2019s Therapy via Wnt Signaling Modulation"],"prefix":"10.1007","volume":"62","author":[{"given":"Suman","family":"Manandhar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasada Chowdari","family":"Gurram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Govindula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shama Prasada","family":"Kabekkodu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2017-9533","authenticated-orcid":false,"given":"K Sreedhara Ranganath","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,17]]},"reference":[{"key":"5047_CR1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2018.4032","author":"C Wang","year":"2018","unstructured":"Wang C, Cai X, Hu W et al (2018) Investigation of the neuroprotective effects of crocin via antioxidant activities in HT22 cells and in mice with Alzheimer\u2019s disease. 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