Lysosomal dysregulation in the murine AppNL-G-F/NL-G-F model of Alzheimer’s disease

Abstract Lysosomal network dysfunction is a prominent feature of Alzheimer’s disease. Although transgenic mouse models of Alzheimer’s disease are known to model some aspects of lysosomal network dysfunction, the lysosomal network has not yet been examined in the knock-in AppNL-G-F/NL-G-F mouse. We aimed to determine whether AppNL-G-F/NL-G-F mice exhibit disruptions to the lysosomal network in the brain. Lysosome-associated membrane protein 1 and cathepsins B, L and D accumulated at amyloid beta plaques in the AppNL-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. AppNL-G-F/NL-G-F mice also exhibited elevated activity of β-hexosaminidase and cathepsins D/E and elevated levels of selected lysosomal network proteins, namely cathepsin D and LC3-II in the cerebral cortex, as determined by western blot. Elevation of cathepsin D did not change the extent of co-localisation between cathepsin D and lysosome-associated membrane protein 1 in the AppNL-G-F/NL-G-F mice. These findings demonstrate that perturbations of the lysosomal network occur in the AppNL-G-F/NL-G-F mouse model, further validating its use an animal model of pre-symptomatic Alzheimer’s disease.