Endolysosome and Autolysosome Dysfunction in Alzheimer's Disease: Where Intracellular and Extracellular Meet

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Disturbed proteostasis as reflected by a massive accumulation of misfolded protein aggregates is a central feature in Alzheimer's disease. Proteostatic disturbances may be caused by a shift in protein production and clearance. Whereas rare genetic causes of the disease affect the production side, sporadic cases appear to be directed by dysfunction in protein clearance. This review focusses on the involvement of lysosome-mediated clearance. Autophagy is a degradational system where intracellular components are degraded by lysosomal organelles. In addition, "outside-to-inside" trafficking through the endosomes converges with the autolysosomal pathway, thereby bringing together intracellular and extracellular components. Recent findings demonstrate that disturbance in the endo- and autolysosomal pathway induces "inside-to-outside" communication via induction of unconventional secretion, which may bear relevance to the spreading of disease pathology through the brain. The involvement of these pathways in the pathogenesis of the disease is discussed with an outlook to the opportunities it provides for diagnostics as well as therapeutic interventions.

Original languageEnglish
Pages (from-to)639-648
Number of pages10
JournalCNS Drugs
Issue number7
Publication statusPublished - Jul 2019


Opens access was paid by Vrije Universiteit Amsterdam, The Netherlands. JvW has received research funding from Alzheimer Nederland (WE.03-2016-05), Alzheimer Association (AARG-17-498856) with instrument support of ZonMW (91111009). WS has received research funding from ZonMW Memorabel/Alzheimer Nederland (Deltaplan Dementie) 733050101, ZonMW/Stichting Proefdiervrij MKMD 114022506, Health Holland (Stichting LSH-TKI) LSHM17104 & LSHM18024, Weston Brain Institute NR160014, Alzheimer Nederland WE.03-2017-10, and Joint Programme-Neurodegenerative Disease Research (NAB3) JPCOFUND_FP-829-031.

FundersFunder number
Alzheimer AssociationAARG-17-498856
Health HollandLSHM17104, LSHM18024
ZonMW Memorabel/Alzheimer NederlandMKMD 114022506, 733050101
Weston Brain InstituteJPCOFUND_FP-829-031, NR160014


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