Amyloid-β (Aβ) accumulation in the brain is a pathological hallmark of Alzheimer’s disease (AD). Endoplasmic reticulum (ER) stress has been implicated in aetiology of neurodegenerative disorders. We studied the involvement of ER stress in Aβ-induced neuronal degeneration in rat brain to correlate it with cellular and molecular modifications in Aβ-induced Alzheimer’s like neuropathological process. Aβ _(1-42) (5 μg) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats. Acetylcholinesterase (AChE) activity and histological alterations were observed in different brain regions. ER stress-associated proteins- glucose regulated protein-78 (GRP78), eukaryotic translation initiation factor-2α (eIF2α) and growth arrest and DNA damage-inducible protein-153 (GADD153), neuronal marker- microtubule associated protein-2 (MAP-2) and microglial protein- ionized calcium binding adaptor molecule-1 (Iba-1) were measured by western blot. Reduced glutathione (GSH), nitrite level and levels of caspase-12 and caspase-3 were also measured. ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneally, ip) was used to assess the specific role of ER stress. Aβ _(1-42)-induced increase in AChE activity, GRP78 and GADD protein levels, dephosphorylation of eIF2-α and caspase-12 and caspase-3 levels and decrease in GSH and MAP-2 levels were attenuated by salubrinal. Increase in Iba-1 protein and nitrite levels after Aβ _(1-42) administration were partially attenuated by salubrinal. Aβ _(1-42)-induced histological alterations were correlated with findings of ER stress. Results of present study implicate ER stress as a potential molecular mechanism in Aβ-induced Alzheimer’s like neuropathology which could serve as surrogate biomarker for study of AD progression and efficacy of therapeutic interventions for AD management.

大脑中淀粉样蛋白-β (Aβ) 的积累是阿尔茨海默病 (AD) 的病理标志。内质网 (ER) 应激与神经退行性疾病的病因有关。我们研究了 ER 应激在大鼠脑中 Aβ 诱导的神经元变性中的参与，以将其与 Aβ 诱导的阿尔茨海默病样神经病理过程中的细胞和分子修饰相关联。Aβ _(1-42)(5 μg) 通过双侧脑室内 (icv) 注射在成年雄性 Wistar 大鼠的大脑中给药。在不同的大脑区域中观察到乙酰胆碱酯酶 (AChE) 活性和组织学改变。ER 应激相关蛋白-葡萄糖调节蛋白-78 (GRP78)、真核翻译起始因子-2α (eIF2α) 和生长停滞和 DNA 损伤诱导蛋白-153 (GADD153)、神经元标记物-微管相关蛋白-2 (MAP- 2) 和小胶质蛋白电离钙结合接头分子-1 (Iba-1) 通过蛋白质印迹法测量。还测量了还原型谷胱甘肽 (GSH)、亚硝酸盐水平以及 caspase-12 和 caspase-3 的水平。ER 应激抑制剂，salubrinal（1 毫克/千克，腹腔注射，ip）用于评估 ER 应激的具体作用。Aβ _(1-42)诱导的 AChE 活性增加、GRP78 和 GADD 蛋白水平、eIF2-α 和 caspase-12 和 caspase-3 水平的去磷酸化以及 GSH 和 MAP-2 水平的降低被 Salubrinal 减弱。Salubrinal 可部分减弱Aβ _(1-42)给药后 Iba-1 蛋白和亚硝酸盐水平的增加。Aβ _(1-42)诱导的组织学改变与内质网应激的发现相关。本研究的结果表明，内质网应激是 Aβ 诱导的阿尔茨海默病样神经病理学的潜在分子机制，可以作为研究 AD 进展和治疗干预对 AD 管理的疗效的替代生物标志物。