Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Present Address: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Acta Neuropathol Commun. 2017 Jun 24;5(1):52. doi: 10.1186/s40478-017-0453-5.
The immunoproteasome (iP) represents a specialized type of proteasomes, which plays an important role in the clearance of oxidant-damaged proteins under inflammatory and pathological conditions determining the outcome of various diseases. In Alzheimer's disease (AD)-like APPPS1 mice Aβ-deposition is paralleled by iP upregulation, most likely mediated through type I interferon induction. To define the impact of increased iP expression we crossed APPPS1 mice with mice deficient in the iP subunit LMP7 resulting in impaired iP function. While LMP7 deficient APPPS1 mice showed no major change in cerebral Aβ-pathology, we observed an altered cytokine response in microglia isolated from LMP7 deficient APPPS1 mice compared to LMP7 expressing APPPS1 control mice. The altered microglial cytokine profile upon iP deficiency in the presence of extracellular Aβ-pathology was associated with an improvement of Aβ-associated cognitive deficits typically present in APPPS1 mice. Our findings suggest a role for iP in the regulation of the innate immune response towards extracellular Aβ-pathology and indicate that inhibition of iP function can modulate the cognitive phenotype upon overexpression of Aβ.
免疫蛋白酶体 (iP) 代表一种特殊类型的蛋白酶体，在炎症和病理条件下清除氧化应激损伤的蛋白质中发挥重要作用，决定着各种疾病的结局。在阿尔茨海默病 (AD) 样 APPPS1 小鼠中，Aβ 沉积伴随着 iP 的上调，这很可能是通过 I 型干扰素诱导介导的。为了确定 iP 表达增加的影响，我们将 APPPS1 小鼠与缺乏 iP 亚基 LMP7 的小鼠进行了杂交，导致 iP 功能受损。虽然 LMP7 缺陷型 APPPS1 小鼠的大脑 Aβ 病理学没有发生重大变化，但与 LMP7 表达的 APPPS1 对照小鼠相比，我们观察到从 LMP7 缺陷型 APPPS1 小鼠分离的小胶质细胞中的细胞因子反应发生了改变。在存在细胞外 Aβ 病理学的情况下，iP 缺乏时改变的小胶质细胞细胞因子谱与 APPPS1 小鼠中常见的 Aβ 相关认知缺陷的改善相关。我们的研究结果表明，iP 在调节针对细胞外 Aβ 病理学的固有免疫反应中起作用，并表明 iP 功能的抑制可以调节 Aβ 过表达时的认知表型。
