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The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-\u03b2 deposition, glycogen synthase kinase 3 beta (GSK3\u03b2), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K\/AKT\/GSK-3\u03b2\/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10\u00a0weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200\u00a0\u03bcg\/kg\/day sc) or liraglutide (0.6\u00a0mg\/kg\/day sc) for 6\u00a0weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K\/AKT expression while decreasing GSK-3\u03b2\/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.<\/jats:p>","DOI":"10.1007\/s00424-024-02933-0","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T06:40:15Z","timestamp":1711521615000},"page":"779-795","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K\/AKT\/GSK-3\u03b2\/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model"],"prefix":"10.1007","volume":"476","author":[{"given":"Hoda M.","family":"Moghazy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesreen G","family":"Abdelhaliem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherine Ahmed","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1909-242X","authenticated-orcid":false,"given":"Amany","family":"Abdelrahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"2933_CR1","doi-asserted-by":"publisher","unstructured":"2021 Alzheimer\u2019s disease facts and figures (2021) Alzheimers Dement 17:327\u2013406 https:\/\/doi.org\/10.1002\/alz.12328","DOI":"10.1002\/alz.12328"},{"key":"2933_CR2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s10787-019-00681-7","volume":"28","author":"A Akhtar","year":"2020","unstructured":"Akhtar A, Dhaliwal J, Saroj P, Uniyal A, Bishnoi M, Sah SP (2020) Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer\u2019s-like dementia via targeting neuroinflammatory and IRS-1\/PI3K\/AKT\/GSK-3beta pathway. 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