Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India; Currently at the School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
Brain Res Bull. 2020 Dec;165:108-117. doi: 10.1016/j.brainresbull.2020.09.022. Epub 2020 Oct 1.
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 (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 -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 administration were partially attenuated by salubrinal. Aβ -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.
淀粉样蛋白-β（Aβ）在大脑中的积累是阿尔茨海默病（AD）的病理学标志。内质网（ER）应激与神经退行性疾病的发病机制有关。我们研究了 ER 应激在 Aβ诱导的大鼠脑神经元变性中的作用，将其与 Aβ诱导的阿尔茨海默病样神经病理学过程中的细胞和分子变化相关联。通过双侧侧脑室（icv）注射将 Aβ（5μg）给予成年雄性 Wistar 大鼠脑内。观察不同脑区乙酰胆碱酯酶（AChE）活性和组织学改变。通过 Western blot 测定 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）、神经元标志物-微管相关蛋白-2（MAP-2）和小胶质细胞蛋白-钙结合衔接蛋白-1（Iba-1）。还测定了还原型谷胱甘肽（GSH）、亚硝酸盐水平以及 caspase-12 和 caspase-3 的水平。使用内质网应激抑制剂 salubrinal（1mg/kg，腹腔内注射，ip）来评估 ER 应激的特定作用。Aβ诱导的 AChE 活性、GRP78 和 GADD 蛋白水平增加、eIF2-α去磷酸化和 caspase-12 和 caspase-3 水平降低以及 GSH 和 MAP-2 水平降低，均被 salubrinal 减弱。Aβ给药后 Iba-1 蛋白和亚硝酸盐水平的增加部分被 salubrinal 减弱。Aβ诱导的组织学改变与 ER 应激的发现相关。本研究结果表明 ER 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，可作为 AD 进展和 AD 治疗干预效果研究的替代生物标志物。
