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Background <p>Alzheimer’s disease (AD) is the most common cause of dementia, with sporadic AD (sAD) accounting for over 90% of cases. Intracerebroventricular streptozotocin (STZ) models show poor reproducibility in females, limiting translational relevance. The intrahippocampal (IH) STZ approach provides improved regional specificity, yet female models remain underexplored despite higher AD prevalence in women.&#xa0;This study was aimed at establishing a female sAD model using bilateral IH-STZ injection and characterizing early behavioral and molecular changes at 7-day intervals (L7) and 14-day intervals (L14).</p> Methods and Materials <p>Female Sprague–Dawley rats were assigned to the Sham L7, Sham L14, STZ L7, and STZ L14 groups. Rats underwent bilateral hippocampal injections, with the sham group receiving phosphate-buffered saline (PBS) and the STZ group receiving STZ (3&#xa0;mg/kg bw). After 7-day intervals or 14-day intervals, behavioral assessments of anxiety, locomotion, recognition memory, and spatial learning and memory were conducted, followed by Western blot analysis of hippocampal and cortical APP and tau oligomers.</p> Results <p>STZ L7 showed increased anxiety-like behavior (p &lt; 0.05), impaired recognition memory (p &lt; 0.05), delayed spatial learning with reduced memory retention (p &lt; 0.05), and reduced cortical APP expression (p &lt; 0.05). Meanwhile, STZ L14 exhibited increased anxiety-like behavior with hyperlocomotion (p &lt; 0.05), impaired recognition memory (p &lt; 0.05), persistent deficits in spatial learning and memory retention (p &lt; 0.05), an increase in hippocampal APP expression and tau oligomerization (p &lt; 0.05), and a reduction in cortical APP expression (p &lt; 0.05).</p> Conclusions <p>Bilateral IH-STZ administration induces sAD-like behavioral impairments and region-specific APP and tau pathology in female rats, with the 14-day post-injection interval showing pronounced AD-related behavioral and molecular alterations.</p>

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Establishing a female rat model of sporadic Alzheimer’s disease via intrahippocampal streptozotocin injection

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Muhamad Kamal Zakaria,
  • Nurul Aqmar Mohd Nor Hazalin,
  • Hanish Singh Jayasingh Chellammal,
  • Gurmeet Kaur Surindar Singh

摘要

Background

Alzheimer’s disease (AD) is the most common cause of dementia, with sporadic AD (sAD) accounting for over 90% of cases. Intracerebroventricular streptozotocin (STZ) models show poor reproducibility in females, limiting translational relevance. The intrahippocampal (IH) STZ approach provides improved regional specificity, yet female models remain underexplored despite higher AD prevalence in women. This study was aimed at establishing a female sAD model using bilateral IH-STZ injection and characterizing early behavioral and molecular changes at 7-day intervals (L7) and 14-day intervals (L14).

Methods and Materials

Female Sprague–Dawley rats were assigned to the Sham L7, Sham L14, STZ L7, and STZ L14 groups. Rats underwent bilateral hippocampal injections, with the sham group receiving phosphate-buffered saline (PBS) and the STZ group receiving STZ (3 mg/kg bw). After 7-day intervals or 14-day intervals, behavioral assessments of anxiety, locomotion, recognition memory, and spatial learning and memory were conducted, followed by Western blot analysis of hippocampal and cortical APP and tau oligomers.

Results

STZ L7 showed increased anxiety-like behavior (p < 0.05), impaired recognition memory (p < 0.05), delayed spatial learning with reduced memory retention (p < 0.05), and reduced cortical APP expression (p < 0.05). Meanwhile, STZ L14 exhibited increased anxiety-like behavior with hyperlocomotion (p < 0.05), impaired recognition memory (p < 0.05), persistent deficits in spatial learning and memory retention (p < 0.05), an increase in hippocampal APP expression and tau oligomerization (p < 0.05), and a reduction in cortical APP expression (p < 0.05).

Conclusions

Bilateral IH-STZ administration induces sAD-like behavioral impairments and region-specific APP and tau pathology in female rats, with the 14-day post-injection interval showing pronounced AD-related behavioral and molecular alterations.