Lysosomal Dysregulation in the Murine AppNL-G-F/NL-G-F Model of Alzheimer's Disease

Lysosomal network dysfunction is a prominent feature of Alzheimer's disease (AD). Although transgenic mouse models of AD are known to model some aspects of lysosomal network dysfunction, the lysosomal network has not yet been examined in the knock-in App(NL-G-F/NL-G-F) mouse. We aimed to determine whether App(NLG-F/NL-G-F) mice exhibit disruptions to the lysosomal network in the brain. Lysosome-associated membrane protein 1 (LAMP1) and cathepsins B, L and D accumulated at amyloid beta plaques in the AppN(L-G-F/NL-G-)F mice, as occurs in human Alzheimer's patients. The accumulation of these lysosomal proteins occurred early in the development of neuropathology, presenting at the earliest and smallest amyloid beta plaques observed. App(NL-G-F/NL-G-F) mice also exhibited elevated activity of beta-hexosaminidase and cathepsins D/E and elevated levels of selected lysosomal network proteins, namely LAMP1, cathepsin D and microtubule-associated protein light chain 3 (LC3-II) in the cerebral cortex, as determined by western blot. Elevation of cathepsin D did not change the extent of colocalisation between cathepsin D and LAMP1 in the App(NL-G-F/NL-G-F) mice. These findings demonstrate that perturbations of the lysosomal network occur in the App(NL-G-F/NL-G-F) mouse model, further validating its use an animal model of pre-symptomatic AD. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.