Lysosomal Dysregulation in the Murine AppNL-G-F/NL-G-F Model of Alzheimer's Disease. (1st March 2020) - Whyte, Lauren S.
Highlights: LAMP1 accumulates at amyloid beta plaques in App NL-G-F/NL-G-F (knock-in) mouse brain. Lysosomal hydrolases are enriched at amyloid beta plaques in App NL-G-F/NL-G-F mice. Some lysosomal network proteins are elevated in App NL-G-F/NL-G-F cortex. Lysosomal network dysfunction in App NL-G-F/NL-G-F mice resembles human AD. Abstract: 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 NL-G-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 App NL-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 β-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 co-localisation 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.