Attia_2026_Metab.Brain.Dis_41_

BACKGROUND: Despite numerous milestones in Alzheimer's disease (AD) research, the disease remains incurable, with a high prevalence and significant financial burdens. As a result, researchers are keen to look for new medications that can help manage or prevent the disease. MATERIALS AND METHODS: The effects of long-term exposures to tirzepatide, a novel dual GIP/GLP-1 receptor agonist, on neurotoxicity and behavioral changes in the D-galactose/aluminium chloride (D-gal/AlCl(3))-induced rats' AD-like pathological model were evaluated. Additionally, we investigated the underlying mechanism for tirzepatide's protective effects against neurotoxicity caused by D-gal/AlCl(3). RESULTS AND CONCLUSION: The present findings show that long-term administration of tirzepatide effectively reduced D-gal/AlCl(3)-induced AD-like neuronal and behavioral deficits and improved rats' learning, spatial memory, and locomotor activity. Tirzepatide restored the aberrant levels of acetylcholine, Abeta1-42, and pTau proteins, major AD hallmarks. Tirzepatide can alleviate behavioral impairments in D-gal/AlCl(3)-exposed rats by lowering acetylcholinesterase activation and inflammatory markers COX-2, IL-6, and TNF-alpha levels. This suggests that tirzepatide may alleviate inflammation, leading to restoring the level of acetylcholine and increasing the expression of the neurotrophin BDNF to reduce Abeta-induced neurodegeneration and apoptosis in rats exposed to D-gal/AlCl(3). The neuroprotective effect of tirzepatide was also confirmed by lowering the histopathological alterations generated by D-gal/AlCl(3) administration, highlighting the possibility of using tirzepatide as a therapeutic candidate to treat AD.