Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder marked by progressive loss of cognitive function. The main neuropathological AD features are the deposition of β-amyloid (Aβ) protein (Camargo et al., 2022) and hyperphosphorylated tau protein (Azarafrouz et al., 2022) in the brain. Further, intra- and extra-cellular accumulation of fibrillar aggregates leads to downstream pathologies such as cholinergic system dysfunction, oxidative stress, inflammation, and death of neurons by apoptosis(Anand et al., 2014; Eskandari et al., 2023). The severity of cognitive impairments in patients with AD is associated with the extent of the pathophysiological events mentioned. The two types of AD including familial AD and sporadic AD differ in the age of onset and course of the disease. Familial AD that has a genetic origin, accounts for less than 1% of cases, while sporadic AD that emerges at later ages represents the dominant part (Sirkis et al., 2022). Unfortunately, no disease-modifying treatments are available that would delay or prevent AD progression to date. Hence, identifying its underlying mechanisms and discovering more effective drugs remain an important issue for the definitive treatment of AD. To this end, experimental animal models of AD are extensively used. The intracerebroventricular (ICV) administration of streptozotocin (STZ) is a widely used animal model to mimic the pathology related to sporadic AD (Salkovic-Petrisic et al., 2013). ICV-STZ injection in rodents results in sporadic AD-like pathology, including oxidative stress, microglia activation, cholinergic damage, and synaptic dysfunction as well as memory and learning impairment, approximately two weeks after injection (Gao et al., 2014; Kamat, 2015; Rai et al., 2013). STZ causes insulin deficiency, which disrupts the insulin receptor signaling pathway, and a decrease in the GSK-3alpha/beta ratio (phosphorylated/total). This in turn stimulates NF-kB protein and increases Aβ accumulation and tau phosphorylation (Singh and Singh, 2023; Yamini et al., 2022). As a result, the integrity of neurons is altered, leading to neurodegeneration. Besides, neuroinflammation caused by high concentrations of proinflammatory cytokines such as TNF-α and IL-1β is associated with cognitive impairments in AD, and the same is acknowledged to occur in the ICV-STZ AD model (Masoumi et al., 2018; Yamini et al., 2018) .

Fibroblast growth factor 18 (FGF18), a glycosylated secretory protein, is an anabolic growth factor involved in cartilage homeostasis (Lu and Lin, 2021). FGF18 has also been found to be expressed in the brain and is mainly involved in midbrain development (Liu et al., 2003). Earlier in vitro studies have shown that FGF18 stimulated neurite outgrowth and had a protective effect against 6-hydroxydopamine (6-OHDA) induced neurotoxicity (Guo et al., 2017b; Ohbayashi et al., 1998). In addition, animal models have shown that FGF18 has a neuroprotective effect against ischemic damage and parkinsonian neurodegeneration (Ellsworth et al., 2003; Guo et al., 2017b). Remarkably, Cavallaro et al. reported that exogenous FGF18 treatment enhanced rats' spatial learning abilities (Cavallaro et al., 2002). However, whether FGF18 exhibits neuroprotective effects have yet to be evaluated in animal models of AD. Therefore, the primary goal of the current study was to assess the effects of FGF18 on the behavioral and neuropathological changes in the rat model of STZ-induced AD.