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• LAMP1 accumulates at amyloid beta plaques in AppNL-G-F/NL-G-F (knock-in) mouse brain. • Lysosomal hydrolases are enriched at amyloid beta plaques in AppNL-G-F/NL-G-F mice. • Some lysosomal network proteins are elevated in AppNL-G-F/NL-G-F cortex. • Lysosomal network dysfunction in AppNL-G-F/NL-G-F mice resembles human AD. 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 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 (LAMP1) 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 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 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 AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. [ABSTRACT FROM AUTHOR]