School of Pharmacy, Anhui Medical University, 81 Mei-Shan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial laboratory of inflammatory and immunity disease, Anhui Institute of Innovative Drugs, Hefei, China.
Department of Laboratory Animal Science, Fudan University, Shanghai 200032, China.
Biomed Pharmacother. 2022 Sep;153:113375. doi: 10.1016/j.biopha.2022.113375. Epub 2022 Jul 11.
To 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.
An 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 (Aβ), 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), Aβ, p-Tau(Ser396), Syt-1, BDNF were measured via immunofluorescence staining.
STZ/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, Aβ, 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.
STZ/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.
建立阿尔茨海默病（AD）小鼠模型，观察双侧侧脑室注射链脲佐菌素（STZ/I.C.V）引起的行为学变化和脑内分子变化，探讨 AD 的潜在发病机制。
通过 STZ/I.C.V 建立 AD 小鼠模型。通过旷场试验（OFT）、新物体识别试验（NOR）和悬尾试验（TST）观察行为学表现。通过 qPCR 和 Western blot 检测海马组织中白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）和肿瘤坏死因子α（TNF-α）的 mRNA 和蛋白表达。采用 Western blot 检测β-淀粉样蛋白 1-42（Aβ）、磷酸化 Tau 蛋白（p-Tau（Ser396））、Tau5、β 位淀粉样前体蛋白裂解酶（BACE）、胰岛素受体底物 1（IRS1）、脑源性神经营养因子（BDNF）、Copine6、突触结合蛋白 1（Syt-1）、突触核蛋白 1（synapsin-1）、磷酸肌醇 3 激酶（PI3K）、丝氨酸/苏氨酸激酶（Akt）、磷酸化丝氨酸/苏氨酸激酶（p-Akt（Ser473））、髓系细胞触发受体 1/2（TREM1/2）的表达，采用免疫荧光染色检测神经胶质纤维酸性蛋白（GFAP）、离子钙结合接头分子 1（IBA1）、Aβ、p-Tau（Ser396）、Syt-1、BDNF 的表达。
STZ/I.C.V 诱导的 AD 样神经精神行为改变，表现为学习记忆能力受损，自发运动和探索行为减少。模型小鼠海马组织中 BACE、Aβ、p-Tau（Ser396）和 TREM2 的表达明显增加，而 IRS1、BDNF、Copine6、Syt-1、synapsin-1、PI3K、p-Akt（Ser473）和 TREM1 的表达则降低。此外，模型小鼠海马组织中星形胶质细胞和小胶质细胞过度激活，IL-1β、IL-6 和 TNF-α 的 mRNA 和蛋白表达增加。
STZ/I.C.V 是诱导 AD 小鼠模型的有效方法，不仅具有 AD 样神经精神行为，还具有典型的 AD 样神经病理学特征，包括神经纤维缠结、β-淀粉样蛋白（Aβ）沉积、神经炎症和突触可塑性失衡。
