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Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
2014 (English)In: Current pharmaceutical design, ISSN 1381-6128, Vol. 20, no 15, 2458-2468 p.Article in journal (Refereed) Published
Abstract [en]

The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

Place, publisher, year, edition, pages
Bentham Science Publishers , 2014. Vol. 20, no 15, 2458-2468 p.
Keyword [en]
Alzheimers disease; lysosome; proteasome; beta-amyloid; neuron-to-neuron transfer; degradation
National Category
Cell and Molecular Biology
URN: urn:nbn:se:liu:diva-107844DOI: 10.2174/13816128113199990501ISI: 000336169300002PubMedID: 23859554OAI: diva2:727875
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2015-08-10Bibliographically approved

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Agholme, LottaHallbeck, Martin
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Division of Cell BiologyFaculty of Health SciencesDivision of Inflammation MedicineDepartment of Clinical Pathology and Clinical Genetics
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