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Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Author(s) -
Whyte Lauren S.,
Lau Adeline A.,
Hemsley Kim M.,
Hopwood John J.,
Sargeant Timothy J.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13935
Subject(s) - lysosome , autophagy , endocytosis , lysosomal storage disease , disease , lysosomal storage disorders , pathogenesis , tfeb , alzheimer's disease , microbiology and biotechnology , biology , dementia , amyloid (mycology) , amyloid precursor protein , neuroscience , medicine , genetics , enzyme , immunology , biochemistry , pathology , cell , botany , apoptosis
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.