OP3 - Impact of the transcription factor NRF2 in the modulation of autophagy on TAU and β-amyloid pathology in a combined mouse model of Alzheimer’s disease

Abstract

NRF2 might orchestrate a defensive response against proteinopa­thies such as Alzheimer’s disease (AD). Indeed, a bioinformatics analysis allowed us to identify several putative ARE-containing autophagy genes whose expression was next confirmed to be regulated by NRF2 in vitro. To explore the relevance of NRF2 in this context, we generated a new AD mouse model consisting on expression of human APPV717I and TAUP301L in the wild type background (biAT) and in Nrf2-knockout mice (triAT). NRF2-deficiency aggravated the long term potentiation defects and impaired spatial memory (Morris water maze). The levels of pro-inflammatory markers as well as astrogliosis and microgliosis were exacerbated in the biAT animals compared to age-matched triAT mice. Intracellular insoluble TAU aggregates were more evident in hippocampus of triAT mice. All mice developed Aβ plaques after 13-14 months, but Nrf2-/- mice developed fewer plaques and a larger number of intracellular APP-positive granules. Immuno-colocalization analyses showed that these aggregates were contained in autophagy vesicles (p62, NDP-52, etc), but triAT mice showed a lower colocalization of APP with these markers, suggesting alterations in the autophagy flux and secretion. These animals will be an excellent tool to study the relevance of NRF2 as a drug target in AD and other proteinopathies.