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Background <p>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.</p> Materials and methods <p>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<sub>3</sub>)-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<sub>3</sub>.</p> Results and conclusion <p>The present findings show that long-term administration of tirzepatide effectively reduced D-gal/AlCl<sub>3</sub>-induced AD-like neuronal and behavioral deficits and improved rats' learning, spatial memory, and locomotor activity. Tirzepatide restored the aberrant levels of acetylcholine, Aβ1-42, and pTau proteins, major AD hallmarks. Tirzepatide can alleviate behavioral impairments in D-gal/AlCl<sub>3</sub>-exposed rats by lowering acetylcholinesterase activation and inflammatory markers COX-2, IL-6, and TNF-α 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 Aβ-induced neurodegeneration and apoptosis in rats exposed to D-gal/AlCl<sub>3</sub>. The neuroprotective effect of tirzepatide was also confirmed by lowering the histopathological alterations generated by D-gal/AlCl<sub>3</sub> administration, highlighting the possibility of using tirzepatide as a therapeutic candidate to treat AD.</p>

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Tirzepatide attenuates neurotoxicity by suppressing inflammation, apoptosis and restoring neurotrophin expression in an Alzheimer’s disease-like rat model

  • 期刊论文

  • 发表日期：

    2026年5月19日

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  • Mohamed S.M. Attia,
  • Sheikh F. Ahmad,
  • Ahmed Nadeem,
  • Mushtaq A. Ansari,
  • Mohammed A. Al-Hamamah,
  • Gamaleldin I. Harisa,
  • Saleh A. Bakheet,
  • Talha Bin Emran,
  • Tanveer Singh,
  • Sabry M. Attia

摘要

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/AlCl3)-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/AlCl3.

Results and conclusion

The present findings show that long-term administration of tirzepatide effectively reduced D-gal/AlCl3-induced AD-like neuronal and behavioral deficits and improved rats' learning, spatial memory, and locomotor activity. Tirzepatide restored the aberrant levels of acetylcholine, Aβ1-42, and pTau proteins, major AD hallmarks. Tirzepatide can alleviate behavioral impairments in D-gal/AlCl3-exposed rats by lowering acetylcholinesterase activation and inflammatory markers COX-2, IL-6, and TNF-α 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 Aβ-induced neurodegeneration and apoptosis in rats exposed to D-gal/AlCl3. The neuroprotective effect of tirzepatide was also confirmed by lowering the histopathological alterations generated by D-gal/AlCl3 administration, highlighting the possibility of using tirzepatide as a therapeutic candidate to treat AD.