First unified time-course of Alzheimer’s-like pathology in the intracerebroventricular streptozotocin-rat model: A systematic review

Abstract

This systematic review investigates the timeline of Alzheimer’s disease (AD)-like changes in the intracerebroventricular streptozotocin (ICV-STZ) rat model, a key tool for studying sporadic, non-genetic forms of AD. Following PRISMA guidelines, we analyzed 402 studies to characterize the progression of key pathological features, including cognitive deficits, insulin resistance, neurodegeneration, neuroinflammation, oxidative stress, tau pathology, amyloid aggregation, blood-brain barrier (BBB) dysfunction, and alterations in the gut-brain axis. Most studies used young male Wistar rats, revealing a sex and age bias. Results show cognitive impairment beginning within the first 24 h after ICV-STZ administration and persisting beyond 121 days, accompanied by early molecular changes, including disrupted insulin signaling, apoptosis (on day 1), and oxidative stress (on day 7). These events triggered a cascade of neuroinflammation, synaptic loss, tau hyperphosphorylation, amyloid plaque formation/accumulation, and neuronal death that closely resemble human AD. This work provides the first unified time-course of these alterations, confirming the model’s ability to mimic the complexity of AD, while also identifying important gaps, such as its limited use of female and aged rats, underexplored areas like the BBB and gut-brain axis, and specific brain regions that require further investigation. The sporadic AD rat model induced by ICV-STZ serves as a powerful and versatile platform for dissecting the multifactorial nature of AD, identifying early biomarkers, and accelerating the development of targeted and disease-modifying therapies.