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Investigating the role of neuronal oxidative stress in early Alzheimer’s disease pathology
Author(s) -
Foret Morgan K.,
Do Carmo Sonia,
Welikovitch Lindsay A.,
Orciani Chiara,
Cuello A. Claudio
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041171
Subject(s) - oxidative stress , laser capture microdissection , genetically modified mouse , transgene , biology , reactive oxygen species , superoxide dismutase , alzheimer's disease , pathology , amyloid (mycology) , medicine , endocrinology , microbiology and biotechnology , gene expression , biochemistry , disease , gene
Background While the amyloid cascade has driven drug development for decades, alternative mechanisms underlying early Alzheimer’s disease (AD) pathogenesis point towards a role of oxidative stress. Cellular responses to oxidative damage are disrupted in AD, additionally, markers of oxidative damage are elevated in the brains of individuals with mild cognitive impairment and AD as well as in AD animal models. However, the earliest role of oxidative stress that coincides with intraneuronal amyloid beta accumulation preceding plaque deposition and cognitive decline has yet to be elucidated. This study aims to investigate oxidative stress related genes as key drivers of disease mechanisms in the early, pre‐plaque AD pathology. Methods The McGill‐R‐Thy1‐APP transgenic rat model was utilized to study the role of neuronal oxidative stress responses during the early, pre‐plaque amyloid pathology. Hippocampal neurons from 5‐month‐old pre‐plaque transgenic and non‐transgenic control rats were excised using laser capture microdissection. The expression of 84 genes related to antioxidant response and reactive oxygen species metabolism was investigated by qRT‐PCR. Validation at the protein level was performed using immunofluorescence microscopy and biochemical assays. Results At the mRNA level, genes including superoxide dismutase, DNA repair enzymes, and antioxidants such as glutathione reductase were dysregulated in transgenic hippocampal neurons compared to wild type controls. At the protein level, there were increased amounts of DNA repair enzymes in the subiculum of Tg rats, reinforcing the observations made at the mRNA level. Assessments at the protein level of additional targets as well as their correlation with intraneuronal amyloid beta load are ongoing. Conclusions These findings show that genes related to oxidative stress responses are dysregulated specifically in neurons burdened with amyloid peptides during early, pre‐plaque stages of the AD amyloid pathology. This suggests that oxidative stress is an important contributor to the earliest AD pathology.