Does oxidatively damaged DNA drive amyloid-β generation in Alzheimer's disease? A hypothesis.

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.