Bilateral intracerebroventricular injection of streptozotocin induces AD-like behavioral impairments and neuropathological features in mice: Involved with the fundamental role of neuroinflammation

Abstract

ObjectiveTo establish an Alzheimer's disease (AD) mouse model, investigate the behavioral performance changes and intracerebral molecular changes induced by bilateral intracerebroventricular injection of streptozotocin (STZ/I.C.V), and explore the potential pathogenesis of AD. MethodsAn AD mouse model was established by STZ/I.C.V. The behavioral performance was observed via the open field test (OFT), novel object recognition test (NOR), and tail suspension test (TST). The mRNA and protein expressions of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in the hippocampus were measured via qPCR and Western blot. The expression of β-amyloid 1–42 (Aβ1–42), phosphorylated Tau protein (p-Tau (Ser396)), Tau5, β-site amyloid precursor protein (APP) cleaving enzyme (BACE), insulin receptor substrate 1 (IRS1), brain-derived neurotrophic factor (BDNF), Copine6, synaptotagmin-1 (Syt-1), synapsin-1, phosphoinositol 3 kinase (PI3K), serine/threonine kinase (Akt), phosphorylated serine/threonine kinase (p-Akt (Ser473)), triggering receptor expressed on myeloid cells-1/2 (TREM1/2) were detected using Western blot, and the expression of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA1), Aβ1–42, p-Tau(Ser396), Syt-1, BDNF were measured via immunofluorescence staining. ResultsSTZ/I.C.V induced AD-like neuropsychiatric behaviors in mice, as indicated by the impairment of learning and memory, together with the reduced spontaneous movement and exploratory behavior. The expression of BACE, Aβ1–42, p-Tau(Ser396), and TREM2 were significantly increased in the hippocampus of model mice, while the expression of IRS1, BDNF, Copine6, Syt-1, synapsin-1, PI3K, p-Akt(Ser473), and TREM1 were decreased as compared with that of the controls. Furthermore, the model mice presented a hyperactivation of astrocytes and microglia in the hippocampus, accompanied by the increased mRNA and protein expressions of IL-1β, IL-6 and TNF-α. ConclusionSTZ/I.C.V is an effective way to induce AD mice model, with not only AD-like neuropsychiatric behaviors, but also typic AD-like neuropathological features including neurofibrillary tangles, deposit of β-amyloid (Aβ), neuroinflammation, and imbalanced synaptic plasticity.