Cited by 150Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyCalcium signaling and nucleotide metabolism

Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

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Whyte, Lauren S., Lau, Adeline A., Hemsley, Kim M., Hopwood, John J., Sargeant, Timothy J.·2017·Journal of Neurochemistry

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. image

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  • Impairment of protein degradation pathways, including autophagy, is found in a host of neurodegenerative diseases.

    “Impairment of protein degradation pathways, including autophagy (reviewed previously66–68), is found in a host of neurodegenerative diseases.”

    From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [66]

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  1. Wraith J. E. (2004) Clinical Aspects and Diagnosis. In Lysosomal Disorders of the Brain. Oxford University Press, Oxford.

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Authors
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J., & Sargeant, T. J.
Affiliations
South Australian Health and Medical Research Institute (AU)
Corresponding author
Sargeant, Timothy J.
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2017-01-23
Volume
140
Issue
5
Pages
703-717
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
OpenAlex
W2562785312
Cited by
150
References
172
Citations by year
2026: 8 · 2025: 15 · 2024: 14 · 2023: 10 · 2022: 20 · 2021: 24 · 2020: 16 · 2019: 18 · 2018: 21 · 2017: 4
FWCI
1.68
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Australian Rotary Health/Rotary Club of Adelaide
  • Australian Postgraduate Award
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
Alzheimer's disease, lysosomal dysfunction, autophagy, endolysosomal trafficking, amyloid-beta clearance, lysosomal storage disease, lysosomal enzyme trafficking, sporadic Alzheimer's disease, endocytosis
MeSH terms
Alzheimer Disease, Animals, Autophagy, Humans, Lysosomes, Lysosomal Storage Diseases, Nervous System

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