Intracerebroventricular streptozotocin-induced animal model of Alzheimer’s disease: revealing dose optimization, administration regimen, and molecular pathways

Streptozotocin (STZ) is a commonly administered chemical via the intracerebroventricular (ICV) route in rodents to induce Alzheimer’s disease (AD)-like symptoms. Unfortunately, available research articles from different laboratories suggest inconsistency in doses, administration schedules, and target brain regions. For instance, ICV dose varies from 1.5 to 5 mg/kg either unilaterally or bilaterally, for 7 days to 21 days, as a single or multiple injections. Therefore, it is challenging for novice investigators to select the optimal doses, treatment durations, and targeted molecular pathways while employing STZ to induce AD-like conditions in experimental animals. In this background, the information related to the STZ-induced animal model of AD should be available on a single platform to aid researchers in selecting the suitable doses and regimens that suit their research objectives. The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as streptozotocin, intracerebroventricular, dosage optimization, Alzheimer’s disease, neuroinflammation, and oxidative stress. The present review highlights the articles published up to May 2025, with predefined inclusion (ICV-STZ model, cognitive/biochemical outcomes) and exclusion criteria (non-peer-reviewed papers, studies lacking behavioral or molecular endpoints, and studies older than 20 years). We have attempted to present the optimal dose, administration regimen, and biological process for inducing ICV-STZ AD models based on their advantages and limitations. According to the comparative quantitative evaluation of preclinical investigations, bilateral ICV administration of STZ at a cumulative dose of 3 mg/kg (1.5 mg/kg on days 1 and 3) displays the most reliable and physiologically relevant regimen. Studies also demonstrated that between 14 and 21 days after injection, this regimen reliably causes oxidative stress, neuroinflammation, cholinergic dysfunction, and progressive cognitive impairments, offering a balanced picture of physiological, histological, and behavioral alterations. However, unlike transgenic models, the ICV-STZ paradigm generally fails to develop extensive amyloid-beta plaque deposition or well-formed neurofibrillary tangles. Hence, more quantitative investigations are necessary to validate this optimization.