Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons
2014 (English)In: Current pharmaceutical design, ISSN 1381-6128, Vol. 20, no 15, 2458-2468 p.Article in journal (Refereed) Published
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.
Alzheimers disease; lysosome; proteasome; beta-amyloid; neuron-to-neuron transfer; degradation
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-107844DOI: 10.2174/13816128113199990501ISI: 000336169300002PubMedID: 23859554OAI: oai:DiVA.org:liu-107844DiVA: diva2:727875