Abstract

In Alzheimer’s disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient’s Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients.

摘要

在阿尔茨海默病 (AD) 中，β-淀粉样蛋白 (Aβ) 的生成和上游 β-分泌酶 1 (BACE1) 的表达似乎是由氧化应激通过 c-Jun N-末端激酶 (JNK)、p38 和干扰素诱导的，双链 RNA 激活蛋白激酶 (PKR)。此外，包括脂多糖 (LPS) 在内的炎症分子通过核因子-κB (NFκB) 诱导 Aβ 生成的核心基因，例如 BACE1。然而，Aβ 生成的其他触发因素仍然知之甚少，可能代表治疗干预的新机会。基于机制研究和临床前 AD、轻度认知障碍和 AD 患者异位氧化损伤 DNA (oxoDNA) 水平升高，我们假设 oxoDNA 从 AD 的早期阶段开始通过多种途径导致 β-淀粉样变性。OxoDNA 诱导丝裂原活化蛋白激酶激酶激酶 4 (MAP4K4)，从而使大脑对氧化应激诱导的 JNK 活化和 BACE1 转录敏感。它还诱导骨髓分化初级反应 88 (MyD88) 并激活蛋白激酶 CK2，从而增加 NFκB 激活和 BACE1 诱导。OxoDNA 通过核因子红细胞 2 相关因子 2 (Nrf2) 异位定位增加氧化应激，可能增强 JNK 介导的 BACE1 诱导。OxoDNA 也可能通过黑色素瘤 2 (AIM2) 诱导中的缺失来促进 β-淀粉样变性。该假设的可证伪预测包括脱氧核糖核酸酶治疗应降低 Aβ 并可能减缓 AD 患者的认知能力下降。虽然对这一假设的正式检验仍有待执行，一份病例报告发现，在 2 个月时，脱氧核糖核酸酶 I 治疗使严重痴呆的 AD 患者的简易精神状态检查评分从 3 分提高到 18 分。有初步的临床前和临床证据表明，异位氧化损伤的 DNA 可能是一种炎症损伤相关的分子模式，有助于 AD 中的 Aβ 生成，应该正式评估脱氧核糖核酸酶 I，以测试它是否可以降低 Aβ 水平并减缓认知能力下降AD患者。