title: Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
abstract: 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.
authors.affiliation: Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.|School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Lauren S
authors.identifier: 0000-0001-7939-656X
authors.initials: LS
authors.lastname: Whyte
authors.affiliation: Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Adeline A
authors.initials: AA
authors.lastname: Lau
authors.affiliation: Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Kim M
authors.identifier: 0000-0003-1038-9884
authors.initials: KM
authors.lastname: Hemsley
authors.affiliation: Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.affiliation: Lysosomal Diseases Research Unit, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sargeant
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D001343:Autophagy; D006801:Humans; D020140:Lysosomal Storage Diseases, Nervous System / Q000473:pathology / Q000503:physiopathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*
keywords: Alzheimer's disease; dementia; endosome; lysosomal storage disorder; lysosome; neurodegenerative disease